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Sample records for aids-related diffuse large

  1. mTOR activity in AIDS-related diffuse large B-cell lymphoma

    PubMed Central

    Diaz-Perez, Julio A.; Preziosi, Michael; King, Charles C.; Jones, George A.; Jain, Sonia; Sun, Xiaoying; Reid, Erin G.; VandenBerg, Scott; Wang, Huan-You

    2017-01-01

    Background Patients infected with HIV have a significantly increased risk of developing non–Hodgkin lymphomas despite the widespread use of HAART. To investigate mTOR pathway activity in acquired immunodeficiency syndrome (AIDS) related diffuse large B-cell lymphoma AR-DLBCL, we used immunohistochemistry to examine the presence of the phosphorylated 70 ribosomal S6 protein-kinase (p70S6K), an extensively studied effector of mTOR Complex 1 (mTORC1) and the phosphorylated phosphatase and tensin homolog (pPTEN), a negative regulator of mTORC1 pathway. Materials and methods We evaluated tissue samples from 126 patients with AR-DLBCL. Among them, 98 samples were from tissue microarrays (TMAs) supplied by the Aids and Cancer Specimen Resource (ACSR), the remaining 28 samples were from cases diagnosed and treated at the University of California, San Diego (UCSD). The presence of p70S6K was evaluated with two antibodies directed against the combined epitopes Ser235/236 and Ser240/244, respectively; and additional monoclonal anti-bodies were used to identify pPTEN and phosphorylated proline-rich Akt substrate of 40kDa (pPRAS40). The degree of intensity and percentage of cells positive for p70S6K and pPTEN were assessed in all the samples. In addition, a subgroup of 28 patients from UCSD was studied to assess the presence of pPRAS40, an insulin-regulated activator of the mTORC1. The expression of each of these markers was correlated with clinical and histopathologic features. Results The majority of the patients evaluated were males (88%); only two cases (1.6%) were older than 65 years of age. We found high levels of both p70S6K-paired epitopes studied, 48% positivity against Ser235/236 (44% in ACSR and 64% in UCSD group), and 86% positivity against Ser240/244 (82% in ACSR and 100% in UCSD group). We observed more positive cells and stronger intensity with epitope Ser240/244 in comparison to Ser235/236 (p<0.0001). The degree of intensity and percentage of cells positive

  2. Gene Therapy and Combination Chemotherapy in Treating Patients With AIDS-Related Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2017-02-23

    AIDS-Related Burkitt Lymphoma; AIDS-Related Diffuse Large B-cell Lymphoma; AIDS-Related Plasmablastic Lymphoma; AIDS-Related Primary Effusion Lymphoma; HIV Infection; AIDS Related Non-Hodgkin Lymphoma

  3. Population Density and AIDS-Related Stigma in Large-Urban, Small-Urban, and Rural Communities of the Southeastern USA.

    PubMed

    Kalichman, Seth; Katner, Harold; Banas, Ellen; Kalichman, Moira

    2017-02-11

    AIDS stigmas delay HIV diagnosis, interfere with health care, and contribute to mental health problems among people living with HIV. While there are few studies of the geographical distribution of AIDS stigma, research suggests that AIDS stigmas are differentially experienced in rural and urban areas. We conducted computerized interviews with 696 men and women living with HIV in 113 different zip code areas that were classified as large-urban, small-urban, and rural areas in a southeast US state with high-HIV prevalence. Analyses conducted at the individual level (N = 696) accounting for clustering at the zip code level showed that internalized AIDS-related stigma (e.g., the sense of being inferior to others because of HIV) was experienced with greater magnitude in less densely populated communities. Multilevel models indicated that after adjusting for potential confounding factors, rural communities reported greater internalized AIDS-related stigma compared to large-urban areas and that small-urban areas indicated greater experiences of enacted stigma (e.g., discrimination) than large-urban areas. The associations between anticipated AIDS-related stigma (e.g., expecting discrimination) and population density at the community-level were not significant. Results suggest that people living in rural and small-urban settings experience greater AIDS-related internalized and enacted stigma than their counterparts living in large-urban centers. Research is needed to determine whether low-density population areas contribute to or are sought out by people who experienced greater AIDS-related stigma. Regardless of causal directions, interventions are needed to address AIDS-related stigma, especially among people in sparsely populated areas with limited resources.

  4. Vorinostat and Combination Chemotherapy With Rituximab in Treating Patients With HIV-Related Diffuse Large B-Cell Non-Hodgkin Lymphoma or Other Aggressive B-Cell Lymphomas

    ClinicalTrials.gov

    2017-01-31

    AIDS-Related Diffuse Large Cell Lymphoma; AIDS-Related Plasmablastic Lymphoma; AIDS-Related Primary Effusion Lymphoma; Grade 3b Follicular Lymphoma; HIV Infection; Plasmablastic Lymphoma; Primary Effusion Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage II Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Grade 3 Contiguous Follicular Lymphoma; Stage II Grade 3 Non-Contiguous Follicular Lymphoma; Stage II Non-Contiguous Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Grade 3 Follicular Lymphoma

  5. Treatment Option Overview (AIDS Related-Lymphoma)

    MedlinePlus

    ... Childhood Hodgkin Lymphoma Treatment Childhood NHL Treatment Research AIDS-Related Lymphoma Treatment (PDQ®)–Patient Version General Information About AIDS-Related Lymphoma Go to Health Professional Version Key ...

  6. Stages of AIDS-Related Lymphoma

    MedlinePlus

    ... Childhood Hodgkin Lymphoma Treatment Childhood NHL Treatment Research AIDS-Related Lymphoma Treatment (PDQ®)–Patient Version General Information About AIDS-Related Lymphoma Go to Health Professional Version Key ...

  7. Treatment Options for AIDS-Related Lymphoma

    MedlinePlus

    ... Childhood Hodgkin Lymphoma Treatment Childhood NHL Treatment Research AIDS-Related Lymphoma Treatment (PDQ®)–Patient Version General Information About AIDS-Related Lymphoma Go to Health Professional Version Key ...

  8. General Information about AIDS-Related Lymphoma

    MedlinePlus

    ... Childhood Hodgkin Lymphoma Treatment Childhood NHL Treatment Research AIDS-Related Lymphoma Treatment (PDQ®)–Patient Version General Information About AIDS-Related Lymphoma Go to Health Professional Version Key ...

  9. Direct Measurement of Large, Diffuse, Optical Structures

    NASA Technical Reports Server (NTRS)

    Saif, Babak N.; Keski-Kuha, Ritva; Feinberg, Lee; Wyant, J. C.; Atkinson, C.

    2004-01-01

    Digital Speckle Pattern Interferometry (DSPI) is a well-established method for the measurement of diffuse objects in experimental mechanics. DSPIs are phase shifting interferometers. Three or four bucket temporal phase shifting algorithms are commonly used to provide phase shifting. These algorithms are sensitive to vibrations and can not be used to measure large optical structures far away from the interferometer. In this research a simultaneous phase shifted interferometer, PhaseCam product of 4D Technology Corporation in Tucson Arizona, is modified to be a Simultaneous phase shifted Digital Speckle Pattern Interferometer (SDSPI). Repeatability, dynamic range, and accuracy of the SDSPI are characterized by measuring a 5 cm x 5 cm carbon fiber coupon.

  10. Carfilzomib, Rituximab, and Combination Chemotherapy in Treating Patients With Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2017-03-07

    Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

  11. [Successful treatment with hyper-CVAD and highly active anti-retroviral therapy (HAART) for AIDS-related Burkitt lymphoma].

    PubMed

    Suzuki, Kazuhito; Nakazato, Tomonori; Sanada, Yukinari; Mihara, Ai; Tachikawa, Natsuo; Kurai, Hanako; Yoshimura, Yukihiro; Hayashi, Hiroyuki; Yoshida, Sachiko; Kakimoto, Tsunayuki

    2010-03-01

    A 38-year-old man was admitted to our hospital because of continuous fever and right facial palsy. He was diagnosed as HIV positive. Abdominal CT scan showed a large mass in the ascending colon. Gallium scintigraphy demonstrated increased uptake in the ascending colon. Colonoscopy was performed and histological examination of the colon tumor revealed Burkitt's lymphoma (BL). He received highly active anti-retroviral therapy (HAART) and his facial palsy improved. Because CD4 count was significantly low at 31/microl, he was treated with dose-adjusted EPOCH (DA-EPOCH) combined with HAART. Although the tumor was decreased in size by DA-EPOCH, we changed to the combination of hyper-CVAD/MTX-Ara-C alternating therapy with HAART in order to increase dose intensity. Six cycles of hyper-CVAD/MTX-Ara-C were performed and complete remission was obtained. In the HAART era, the survival of patients with AIDS-related diffuse large cell lymphoma (DLCL) improved dramatically, whereas the survival of similarly treated patients with AIDS-related BL remained poor. Our case suggests that intensive chemotherapy with hyper-CVAD/MTX-Ara-C combined with HAART may be well tolerated and effective in AIDS-related BL.

  12. Aids-Related Cancers in Africa

    NASA Astrophysics Data System (ADS)

    Mbulaiteye, Sam M.

    2014-07-01

    Thank you Professor Zichichi for inviting me to give a talk about AIDS-related cancers in Africa. Let me begin by congratulating the team that organized the 46th Session of the Erice International Seminar Series, whose theme is THE ROLE OF SCIENCE IN THE THIRD MILLENIUM. I also congratulate the scientists from 38 countries who are attending these seminars. They are perpetuating the principle of SCIENCE WITHOUT SECRETS in the true spirit espoused by Archimedes, Galileo, and Fermi. It is a wonderful honor for me to be here to shed some light on the health impacts of the HIV epidemic in the area of cancer...

  13. Diffuse reflectance relations based on diffusion dipole theory for large absorption and reduced scattering

    NASA Astrophysics Data System (ADS)

    Bremmer, Rolf H.; van Gemert, Martin J. C.; Faber, Dirk J.; van Leeuwen, Ton G.; Aalders, Maurice C. G.

    2013-08-01

    Diffuse reflectance spectra are used to determine the optical properties of biological samples. In medicine and forensic science, the turbid objects under study often possess large absorption and/or scattering properties. However, data analysis is frequently based on the diffusion approximation to the radiative transfer equation, implying that it is limited to tissues where the reduced scattering coefficient dominates over the absorption coefficient. Nevertheless, up to absorption coefficients of 20 m at reduced scattering coefficients of 1 and 11.5 mm-1, we observed excellent agreement (r2=0.994) between reflectance measurements of phantoms and the diffuse reflectance equation proposed by Zonios et al. [Appl. Opt. 38, 6628-6637 (1999)], derived as an approximation to one of the diffusion dipole equations of Farrell et al. [Med. Phys. 19, 879-888 (1992)]. However, two parameters were fitted to all phantom experiments, including strongly absorbing samples, implying that the reflectance equation differs from diffusion theory. Yet, the exact diffusion dipole approximation at high reduced scattering and absorption also showed agreement with the phantom measurements. The mathematical structure of the diffuse reflectance relation used, derived by Zonios et al. [Appl. Opt. 38, 6628-6637 (1999)], explains this observation. In conclusion, diffuse reflectance relations derived as an approximation to the diffusion dipole theory of Farrell et al. can analyze reflectance ratios accurately, even for much larger absorption than reduced scattering coefficients. This allows calibration of fiber-probe set-ups so that the object's diffuse reflectance can be related to its absorption even when large. These findings will greatly expand the application of diffuse reflection spectroscopy. In medicine, it may allow the use of blue/green wavelengths and measurements on whole blood, and in forensic science, it may allow inclusion of objects such as

  14. Diffuse reflectance relations based on diffusion dipole theory for large absorption and reduced scattering.

    PubMed

    Bremmer, Rolf H; van Gemert, Martin J C; Faber, Dirk J; van Leeuwen, Ton G; Aalders, Maurice C G

    2013-08-01

    Diffuse reflectance spectra are used to determine the optical properties of biological samples. In medicine and forensic science, the turbid objects under study often possess large absorption and/or scattering properties. However, data analysis is frequently based on the diffusion approximation to the radiative transfer equation, implying that it is limited to tissues where the reduced scattering coefficient dominates over the absorption coefficient. Nevertheless, up to absorption coefficients of 20  mm-1 at reduced scattering coefficients of 1 and 11.5  mm-1, we observed excellent agreement (r2=0.994) between reflectance measurements of phantoms and the diffuse reflectance equation proposed by Zonios et al. [Appl. Opt.38, 6628-6637 (1999)], derived as an approximation to one of the diffusion dipole equations of Farrell et al. [Med. Phys.19, 879-888 (1992)]. However, two parameters were fitted to all phantom experiments, including strongly absorbing samples, implying that the reflectance equation differs from diffusion theory. Yet, the exact diffusion dipole approximation at high reduced scattering and absorption also showed agreement with the phantom measurements. The mathematical structure of the diffuse reflectance relation used, derived by Zonios et al. [Appl. Opt.38, 6628-6637 (1999)], explains this observation. In conclusion, diffuse reflectance relations derived as an approximation to the diffusion dipole theory of Farrell et al. can analyze reflectance ratios accurately, even for much larger absorption than reduced scattering coefficients. This allows calibration of fiber-probe set-ups so that the object's diffuse reflectance can be related to its absorption even when large. These findings will greatly expand the application of diffuse reflection spectroscopy. In medicine, it may allow the use of blue/green wavelengths and measurements on whole blood, and in forensic science, it may allow inclusion of objects such as blood stains and cloth at crime

  15. Combination Chemo, Rituximab, and Bevacizumab in Older Patients With Stage II-IV Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2014-05-06

    Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

  16. Large-scale diffusion of entangled polymers along nanochannels

    NASA Astrophysics Data System (ADS)

    Saalwachter, Kay; Lange, Frank; Steinhart, Martin; Judeinstein, Patrick

    2015-03-01

    Confinement-induced changes in polymer mobility are still under active discussion. For weakly interacting poly(butadiene) chains in 100 μm long, 20 and 60 nm wide channels in anodic Al2O3, we here report on the study of the large-scale pore-averaged self diffusion on a μm scale by 1H pulsed-gradient NMR. We find weak indications of an acceleration due to surface-induced disentanglement. Unlike previous reports on polymer diffusion into particle nanocomposites of similar confinement scale, or start-up diffusivities out of even thinner films, we find an MW and temperature independent reduction of diffusivity that is solely determined by the confinement size. We rationalize this trend by a simple volume-average model, which suggests a 20-fold surface-enhanced monomeric friction on the scale of the packing length, which can be compared to a factor of 300 that our model predicts for comparable thin-film data of poly(styrene) on silica.

  17. The Uneven Diffusion of Collaborative Technology in a Large Organization

    NASA Astrophysics Data System (ADS)

    Jarulaitis, Gasparas

    This paper investigates the large-scale diffusion of a collaborative technology in a range of different business contexts. The empirical data used in the article were obtained from a longitudinal (2007-2009) case study of a global oil and gas company (OGC). Our study reports on ongoing efforts to deploy an inte grated collaborative system that uses Microsoft SharePoint (MSP) technology. We assess MSP as a configurational technology and analyze the diffusion of a metadata standard developed in-house, which forms an embedded component of MSP. We focus on two different organizational contexts, namely research and development (R&D) and oil and gas production (OGP), and illustrate the key differences between the ways in which configurational technology is managed and used in these contexts, which results in an uneven diffusion. In contrast with previous studies, we unravel the organizational and technological complexity involved, and thus empirically illustrate the flexibility of large-scale technology and show how the trajectories of the various components are influenced by multiple modes of ordering.

  18. Turbulent diffusion of large solids in a protoplanetary disc

    NASA Astrophysics Data System (ADS)

    Carballido, Augusto; Bai, Xue-Ning; Cuzzi, Jeffrey N.

    2011-07-01

    We study the turbulent diffusion of solids in a protoplanetary disc, in order to discriminate between two existing analytical models of the turbulent diffusion process. These two models predict the same radial turbulent diffusion coefficient Dp, x for small particles (τs≪ 1), but differ in the value of Dp, x for large particles (τs≫ 1, where τs is the dimensionless particle stopping time, closely related to particle radius). The model given by Youdin & Lithwick (YL) takes into account orbital oscillations of the solids, while the other model given by Cuzzi, Dobrovolskis & Champney (CDC) does not. The CDC model predicts ? for τs≫ 1, but the YL model gives ?. To investigate, we perform 3D, magnetohydrodynamic (MHD) numerical simulations. Turbulence in the disc is generated by the magnetorotational instability. The ATHENA code is used to solve the equations of ideal MHD in the shearing-box approximation, which allows us to model a local region of the disc with the relevant orbital dynamics. Solids are represented by Lagrangian particles that interact with the gas through drag, and are also subject to orbital forces. The aerodynamic coupling of particles to the gas is parametrized by τs. In one set of simulations, particle displacements along the radial direction are measured in a shearing box without vertical stratification of the gas density. In another simulation, the vertical component of stellar gravity is included, with a Gaussian gas density vertical profile, but the particle motion is restricted to fixed planes of constant height z. In both cases, the radial diffusion coefficient as a function of stopping time τs is in very good agreement with the YL model. To study particle vertical diffusion, we use the unstratified shearing box, in which we allow the effects of vertical gravity and turbulence on the particles to balance out, resulting in particle layers whose scaleheight varies approximately as ?. Based on this result and YL, we calculate a

  19. Quenched Large Deviations for Interacting Diffusions in Random Media

    NASA Astrophysics Data System (ADS)

    Luçon, Eric

    2017-03-01

    The aim of the paper is to establish a large deviation principle (LDP) for the empirical measure of mean-field interacting diffusions in a random environment. The point is to derive such a result once the environment has been frozen (quenched model). The main theorem states that a LDP holds for every sequence of environment satisfying appropriate convergence condition, with a rate function that does not depend on the disorder and is different from the rate function in the averaged model. Similar results concerning the empirical flow and local empirical measures are provided.

  20. [AIDS related lymphomas: Histopathological subtypes and association with Epstein Barr virus and Human Herpes virus type-8].

    PubMed

    Corti, Marcelo; de Dios Soler, Marcela; Bare, Patricia; Villafañe, María F; De Tezanos Pinto, Miguel; Perez Bianco, Raúl; Narbaitz, Marina

    2010-01-01

    Non-Hodgkin lymphomas (NHL) of the B-cell type are the second most common neoplasm among patients with human immunodeficiency virus (HIV) infection and AIDS. Here, we evaluated 48 cases of AIDS-related lymphomas (ARL) diagnosed at the Histopathological Division of the Instituto de Investigaciones Hematológicas of the National Academy of Medicine. Five were females and 43 were males with a median of age of 37 years at the time of the diagnosis. Micrometer sections were prepared and stained with hematoxilin-eosin; immunohistochemical examination for the presence of Epstein-Barr virus (EBV) was carried out in 48/48 cases. Additionally, biotinilated oligonucleotides were used to determine the presence of DNA of the Human Herpes virus type-8 (HHV-8) in 14/14 biopsy smears corresponding to plasmablastic lymphomas (PL). All were fenotype B cell lymphomas with an aggressive course and advanced neoplasm disease at the time of diagnosis. Virological findings showed the strong association between EBV and AIDS-related NHL. According to the histopathological subtype, the EBV genome was detected in 16/21 (76%) diffuse large B cell lymphomas, 1/3 Burkitt lymphoma and 3/4 (75%) of primary central nervous system lymphomas. Globally, EBV genome was detected in 20/28 NHL of this series. Detection of HHV-8 was negative in all cases of PL. Hodgkin lymphoma were more frequent in males 18/20 (90%), with an aggressive clinical course and a significant predominance of the subtypes associated with worse prognosis (90% of cases). We detected a significant association between EBV and HL (90% of cases). We consider that all cases of AIDS related lymphomas should be assessed for the presence of EBV because its presence may play a role in the prognosis.

  1. AIDS-related mycoses: the way forward.

    PubMed

    Brown, Gordon D; Meintjes, Graeme; Kolls, Jay K; Gray, Clive; Horsnell, William; Achan, Beatrice; Alber, Gottfried; Aloisi, Maria; Armstrong-James, Darius; Beale, Mathew; Bicanic, Tihana; Black, John; Bohjanen, Paul; Botes, Angela; Boulware, David R; Brown, Gordon; Bunjun, Rubina; Carr, William; Casadevall, Arturo; Chang, Christina; Chivero, Ernest; Corcoran, Craig; Cross, Anna; Dawood, Halima; Day, Jeremy; De Bernardis, Flavia; De Jager, Veronique; De Repentigny, Louis; Denning, David; Eschke, Maria; Finkelman, Malcolm; Govender, Nelesh; Gow, Neil; Graham, Lisa; Gryschek, Ronaldo; Hammond-Aryee, Kenneth; Harrison, Tom; Heard, Neil; Hill, Melanie; Hoving, J Claire; Janoff, Edward; Jarvis, Joseph; Kayuni, Sekeleghe; King, Karin; Kolls, Jay; Kullberg, Bart-Jan; Lalloo, David G; Letang, Emilio; Levitz, Stuart; Limper, Andrew; Longley, Nicky; Machiridza, Tendai Rodney; Mahabeer, Yesholata; Martinsons, Neil; Meiring, Susan; Meya, David; Miller, Robert; Molloy, Sile; Morris, Lynn; Mukaremera, Liliane; Musubire, Abdu K; Muzoora, Conrad; Nair, Amy; Nakiwala Kimbowa, Justine; Netea, Mihai; Nielsen, Kirsten; O'hern, Jennifer; Okurut, Samuel; Parker, Arifa; Patterson, Tom; Pennap, Grace; Perfect, John; Prinsloo, Chrisna; Rhein, Joshua; Rolfes, Melissa A; Samuel, Catherine; Schutz, Charlotte; Scriven, James; Sebolai, Olihile M; Sojane, Katlego; Sriruttan, Charlotte; Stead, David; Steyn, Annica; Thawer, Narjis K; Thienemann, Friedrich; Von Hohenberg, Maximilian; Vreulink, Jo-marie; Wessels, Jeannette; Wood, Kathryn; Yang, Yun-liang

    2014-03-01

    The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries.

  2. Lenalidomide in diffuse large B-cell lymphoma.

    PubMed

    Thieblemont, Catherine; Delfau-Larue, Marie-Hélène; Coiffier, Bertrand

    2012-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma (NHL) in adults. Even if the natural history of DLBCL has been improved with the advent of immunochemotherapy, the survival results obtained with current treatment options clearly indicate that new agents or novel approaches are needed. Lenalidomide (Revlimid, Celgene Corporation, Summit, NJ, USA), an analogue of thalidomide, is an immunomodulatory drug with pleiotropic mechanisms of action potentially adding to immunochemotherapy. We present here the biological rational for the use of lenalidomide in DLBCL in light of recent advances in the pathophysiology of the disease and the therapeutic results of the most recent trials published in literature or reported in meetings in relapsed/refractory situations as well as in first-line treatment.

  3. TP53 dysfunction in diffuse large B-cell lymphoma.

    PubMed

    Lu, Ting-Xun; Young, Ken H; Xu, Wei; Li, Jian-Yong

    2016-01-01

    The aberrations of TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers, including malignant lymphomas, especially for diffuse large B cell lymphoma (DLBCL). By regulating many downstream target genes or molecules, TP53 governs major defenses against tumor growth and promotes cellular DNA repair, apoptosis, autophagy, cell cycle arrest, signaling, transcription, immune or inflammatory responses and metabolism. Dysfunction of TP53, including microRNA regulations, copy number alterations of TP53 pathway and TP53 itself, dysregulation of TP53 regulators, and somatic mutations by abnormal TP53 function modes, play an important role in lymphoma generation, progression and invasion. The role of TP53 in DLBCL has been widely explored recently. In this review, we summarized recent advances on different mechanisms of TP53 in DLBCL and new therapeutic approaches to overcome TP53 inactivation.

  4. Small and Large Molecules in the Diffuse Interstellar Medium

    NASA Astrophysics Data System (ADS)

    Oka, Takeshi; Huang, Jane

    2014-06-01

    Although molecules with a wide range of sizes exist in dense clouds (e.g. H(C≡C)_nC≡N with n = 0 - 5), molecules identified in diffuse clouds are all small ones. Since the initial discovery of CH, CN, and CH^+, all molecules detected in the optical region are diatomics except for H_3^+ in the infrared and C_3 in the visible. Radio observations have been limited up to triatomic molecules except for H_2CO and the ubiquitous C_3H_2. The column densities of all molecules are less than 1014 cm-2 with the two exceptions of CO and H_3^+ as well as CH and C_2 in a few special sightlines. Larger molecules with many carbon atoms have been searched for but have not been detected. On the other hand, the observations of a great many diffuse interstellar bands (380 toward HD 204827 and 414 toward HD 183143) with equivalent widths from 1 to 5700 m Å indicate high column densities of many heavy molecules. If an electronic transition dipole moment of 1 Debye is assumed, the observed equivalent widths translate to column densities from 5 × 1011 cm-2 to 3 × 1015 cm-2. It seems impossible that these large molecules are formed from chemical reactions in space from small molecules. It is more likely that they are fragments of aggregates, perhaps mixed aromatic/aliphatic organic nanoparticles (MAONS). MAONS and their large fragment molecules are stable against photodissociation in the diffuse ISM because the energy of absorbed photons is divided into statistical distributions of vibrational energy and emitted in the infrared rather than breaking a chemical bond. We use a simple Rice-Ramsperger-Kassel-Marcus theory to estimate the molecular size required for the stabilization. Snow, T. P. & McCall, B. J. 2006, ARA&A, 44 367 Hobbs, L. M., York, D. G., Snow, T. P., Oka, T., Thorburn, J. A., et al. 2008, ApJ, 680 1256 Hobbs, L. M., York, D. G., Thorburn, J. A., Snow, T. P., Bishof, M., et al. 2009, ApJ, 705 32 Kwok, S. & Zhang, S. 2013, ApJ, 771 5 Freed, K. F., Oka, T., & Suzuki, H

  5. Rituximab and Combination Chemotherapy in Treating Patients With Previously Untreated High- or High-Intermediate-Risk Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2016-03-01

    Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

  6. Oblimersen Sodium and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage I, Stage II, Stage III, or Stage IV Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2012-10-11

    Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

  7. Ibrutinib Before and After Stem Cell Transplant in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

    ClinicalTrials.gov

    2017-04-11

    Activated B-Cell-Like Diffuse Large B-Cell Lymphoma; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Recurrent Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

  8. Relapsed/refractory diffuse large B-cell lymphoma.

    PubMed

    Friedberg, Jonathan W

    2011-01-01

    Despite overall improvements in outcomes of diffuse large B-cell lymphoma (DLBCL), approximately one-third of patients will develop relapsed/refractory disease that remains a major cause of morbidity and mortality. Novel insights from gene-expression analyses have increased our understanding of chemotherapy resistance and yielded rational targets for therapeutic intervention to both prevent and treat relapsed/refractory DLBCL. The clinical approach to relapsed/refractory DLBCL should include high-dose therapy and autologous stem cell transplantation (HD-ASCT) with curative intent in patients without comorbidities. Results from the recently reported CORAL study suggest that patients refractory to rituximab-containing regimens have inferior outcomes with HD-ASCT. Ongoing efforts to improve ASCT include novel conditioning regimens and evaluation of maintenance approaches after ASCT. Unfortunately, because the majority of patients are not eligible for ASCT due to refractory disease or age/comorbidities, these approaches have limited impact. The large group of patients not eligible for ASCT have incurable disease and should be referred for clinical trials of rationally targeted agents.

  9. Cerebral toxoplasmosis in a diffuse large B cell lymphoma patient

    PubMed Central

    Savsek, Lina; Opaskar, Tanja Ros

    2016-01-01

    Background Toxoplasmosis is an opportunistic protozoal infection that has, until now, probably been an underestimated cause of encephalitis in patients with hematological malignancies, independent of stem cell or bone marrow transplant. T and B cell depleting regimens are probably an important risk factor for reactivation of a latent toxoplasma infection in these patients. Case report We describe a 62-year-old HIV-negative right-handed Caucasian female with systemic diffuse large B cell lymphoma who presented with sudden onset of high fever, headache, altered mental status, ataxia and findings of pancytopenia, a few days after receiving her final, 8th cycle of rituximab, cyclophosphamide, vincristine, doxorubicin, prednisolone (R-CHOP) chemotherapy regimen. A progression of lymphoma to the central nervous system was suspected. MRI of the head revealed multiple on T2 and fluid attenuated inversion recovery (FLAIR) hyperintense parenchymal lesions with mild surrounding edema, located in both cerebral and cerebellar hemispheres that demonstrated moderate gadolinium enhancement. The polymerase chain reaction on cerebrospinal fluid (CSF PCR) was positive for Toxoplasma gondii. The patient was diagnosed with toxoplasmic encephalitis and successfully treated with sulfadiazine, pyrimethamine and folic acid. Due to the need for maintenance therapy with rituximab for lymphoma remission, the patient now continues with secondary prophylaxis of toxoplasmosis. Conclusions With this case report, we wish to emphasize the need to consider cerebral toxoplasmosis in patients with hematological malignancies on immunosuppressive therapy when presenting with new neurologic deficits. In such patients, there are numerous differential diagnoses for cerebral toxoplasmosis, and the CNS lymphoma is the most difficult among all to distinguish it from. If left untreated, cerebral toxoplasmosis has a high mortality rate; therefore early recognition and treatment are of essential importance. PMID

  10. Patterns of gallium-67 scintigraphy in patients with acquired immunodeficiency syndrome and the AIDS related complex

    SciTech Connect

    Bitran, J.; Bekerman, C.; Weinstein, R.; Bennett, C.; Ryo, U.; Pinsky, S.

    1987-07-01

    Thirty-two patients with AIDS related complex (ARC) or acquired immunodeficiency syndrome (AIDS) underwent /sup 67/Ga scans as part of their evaluation. Three patterns of /sup 67/Ga biodistribution were found: lymph node uptake alone; diffuse pulmonary uptake; normal scan. Gallium-67 scans were useful in identifying clinically occult Pneumocystis carinii pneumonia in seven of 15 patients with ARC who were asymptomatic and had normal chest radiographs. Gallium scans are a useful ancillary procedure in the evaluation of patients with ARC or AIDS.

  11. Vorinostat, Rituximab, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II, Stage III, or Stage IV Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2016-09-08

    Stage II Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

  12. S0349 Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone With or Without Oblimersen in Treating Patients With Advanced Diffuse Large B-Cell Non-Hodgkin's Lymphoma

    ClinicalTrials.gov

    2013-01-04

    Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

  13. Carfilzomib, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Stage I-IV Diffuse Large B-cell Lymphoma

    ClinicalTrials.gov

    2017-02-15

    CD20 Positive; Recurrent Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Stage I Diffuse Large B-Cell Lymphoma; Stage II Diffuse Large B-Cell Lymphoma; Stage III Diffuse Large B-Cell Lymphoma; Stage IV Diffuse Large B-Cell Lymphoma

  14. R-ICE and Lenalidomide in Treating Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma

    ClinicalTrials.gov

    2017-03-03

    Diffuse Large B-Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

  15. Diffuse Large B-Cell Lymphoma Mimicking Schwannoma of Lumbar Spine

    PubMed Central

    Kim, Seung-Kook; Lee, Sun-Ho; Kim, Eun-Sang

    2016-01-01

    A rare case of solitary diffuse large B-cell lymphoma arising from the lumbar spinal nerve root is reported. A 37-year-old man presented with a 3-month history of progressive numbness and paraparesis in both legs. The initial diagnosis was benign primary intradural extramedullary tumor including schwannoma and meningioma. Histopathological examination revealed diffuse large B-cell lymphoma. While a well-defined T1 isointense mass is common in primary spinal schwannoma, the present case was atypical and had a yellowish neural component. The pathogenesis and radiological findings of spinal diffuse large B-cell lymphoma are discussed and related literature is reviewed. PMID:27437017

  16. Large disparity between gallium and antimony self-diffusion in gallium antimonide.

    PubMed

    Bracht, H; Nicols, S P; Walukiewicz, W; Silveira, J P; Briones, F; Haller, E E

    2000-11-02

    The most fundamental mass transport process in solids is self-diffusion. The motion of host-lattice ('self-') atoms in solids is mediated by point defects such as vacancies or interstitial atoms, whose formation and migration enthalpies determine the kinetics of this thermally activated process. Self-diffusion studies also contribute to the understanding of the diffusion of impurities, and a quantitative understanding of self- and foreign-atom diffusion in semiconductors is central to the development of advanced electronic devices. In the past few years, self-diffusion studies have been performed successfully with isotopically controlled semiconductor heterostructures of germanium, silicon, gallium arsenide and gallium phosphide. Self-diffusion studies with isotopically controlled GaAs and GaP have been restricted to Ga self-diffusion, as only Ga has two stable isotopes, 69Ga and 71Ga. Here we report self-diffusion studies with an isotopically controlled multilayer structure of crystalline GaSb. Two stable isotopes exist for both Ga and Sb, allowing the simultaneous study of diffusion on both sublattices. Our experiments show that near the melting temperature, Ga diffuses more rapidly than Sb by over three orders of magnitude. This surprisingly large difference in atomic mobility requires a physical explanation going beyond standard diffusion models. Combining our data for Ga and Sb diffusion with related results for foreign-atom diffusion in GaSb (refs 8, 9), we conclude that the unusually slow Sb diffusion in GaSb is a consequence of reactions between defects on the Ga and Sb sublattices, which suppress the defects that are required for Sb diffusion.

  17. Epigenetic regulation of HIV, AIDS, and AIDS-related malignancies.

    PubMed

    Verma, Mukesh

    2015-01-01

    Although epigenetics is not a new field, its implications for acquired immunodeficiency syndrome (AIDS) research have not been explored fully. To develop therapeutic and preventive approaches against the human immunodeficiency virus (HIV) and AIDS, it is essential to understand the mechanisms of interaction between the virus and the host, involvement of genetic and epigenetic mechanisms, characterization of viral reservoirs, and factors influencing the latency of the virus. Both methylation of viral genes and histone modifications contribute to initiating and maintaining latency and, depending on the context, triggering viral gene repression or expression. This chapter discusses progress made at the National Institutes of Health (NIH), recommendations from the International AIDS Society Scientific Working Group on HIV Cure, and underlying epigenetic regulation. A number of epigenetic inhibitors have shown potential in treating AIDS-related malignancies. Epigenetic drugs approved by the US Food and Drug Administration and their implications for the eradication of HIV/AIDS and AIDS-related malignancies also are discussed.Past and current progress in developing treatments and understanding the molecular mechanisms of AIDS and HIV infection has greatly improved patient survival. However, increased survival has been coupled with the development of cancer at higher rates than those observed among the HIV/AIDS-negative population. During the early days of the AIDS epidemic, the most frequent AIDS-defining malignancies were Kaposi's sarcoma and non-Hodgkin lymphoma (NHL). Now, with increased survival as the result of widespread use in the developed world of highly active antiretroviral therapy (HAART), non-AIDS defining cancers (i.e., anal, skin, and lung cancers, and Hodgkin disease) are on the increase in HIV-infected populations. The current status of AIDS-related malignancies also is discussed.

  18. Advective-diffusive motion on large scales from small-scale dynamics with an internal symmetry

    NASA Astrophysics Data System (ADS)

    Marino, Raffaele; Aurell, Erik

    2016-06-01

    We consider coupled diffusions in n -dimensional space and on a compact manifold and the resulting effective advective-diffusive motion on large scales in space. The effective drift (advection) and effective diffusion are determined as a solvability conditions in a multiscale analysis. As an example, we consider coupled diffusions in three-dimensional space and on the group manifold SO(3) of proper rotations, generalizing results obtained by H. Brenner [J. Colloid Interface Sci. 80, 548 (1981), 10.1016/0021-9797(81)90214-9]. We show in detail how the analysis can be conveniently carried out using local charts and invariance arguments. As a further example, we consider coupled diffusions in two-dimensional complex space and on the group manifold SU(2). We show that although the local operators may be the same as for SO(3), due to the global nature of the solvability conditions the resulting diffusion will differ and generally be more isotropic.

  19. Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs

    PubMed Central

    Mathur, Rohit; Sehgal, Lalit; Havranek, Ondrej; Köhrer, Stefan; Khashab, Tamer; Jain, Neeraj; Burger, Jan A.; Neelapu, Sattva S.; Davis, R. Eric; Samaniego, Felipe

    2017-01-01

    Histone methylation and demethylation regulate B-cell development, and their deregulation correlates with tumor chemoresistance in diffuse large B-cell lymphoma, limiting cure rates. Since histone methylation status correlates with disease aggressiveness and relapse, we investigated the therapeutic potential of inhibiting histone 3 Lys27 demethylase KDM6B, in vitro, using the small molecule inhibitor GSK-J4. KDM6B is overexpressed in the germinal center B-cell subtype of diffuse large B-cell lymphoma, and higher KDM6B levels are associated with worse survival in patients with diffuse large B-cell lymphoma treated with R-CHOP. GSK-J4-induced apoptosis was observed in five (SU-DHL-6, OCI-Ly1, Toledo, OCI-Ly8, SU-DHL-8) out of nine germinal center B-cell diffuse large B-cell lymphoma cell lines. Treatment with GSK-J4 predominantly resulted in downregulation of B-cell receptor signaling and BCL6. Cell lines expressing high BCL6 levels or CREBBP/EP300 mutations were sensitive to GSK-J4. Our results suggest that B-cell receptor-dependent downregulation of BCL6 is responsible for GSK-J4-induced cytotoxicity. Furthermore, GSK-J4-mediated inhibition of KDM6B sensitizes germinal center B-cell diffuse large B-cell lymphoma cells to chemotherapy agents that are currently utilized in treatment regimens for diffuse large B-cell lymphoma. PMID:27742770

  20. Photodynamic therapy for treatment of AIDS-related mucocutaneous Kaposi's sarcoma (Invited Paper)

    NASA Astrophysics Data System (ADS)

    Schweitzer, Vanessa G.

    1992-06-01

    Since 1975, Phase I/II studies have demonstrated the successfulness of hematoporphyrin derivative photodynamic therapy (PDT) in the treatment of various malignancies of the skin, eye, bladder, lung, and head and neck. Moreover, in 1981 two cases of traditional Western cutaneous Kaposi's sarcoma (TKS) have been treated with photodynamic therapy with both early and late complete response. To date, attempts to cure and palliation of the more aggressive AIDS-related oral Kaposi's sarcoma with conventional radiation, chemotherapy or immunotherapy, or surgical excision have been limited and often associated with debilitating mucositis and further immunosuppression. Certain aspects of photodynamic therapy may be efficacious for treatment of mucocutaneous Kaposi's sarcoma: (1) the selective retention of hematoporphyrin derivative by neoplastic lesions (endothelial cell tumors); (2) a tumor- specific cytotoxic agent (i.e., free oxygen radical); (3) absence of systemic toxicity from immunosuppression; (4) the potential for retreatment without increasing side effects; and (5) porphyrin-mediated photoinactivation of enveloped viruses. Herein presented are seven cases of AIDS-related KS (EKS) with diffuse, superficial, and nodular mucocutaneous lesions treated with dihematoporphyrin derivative and photodynamic therapy with subsequent dramatic early partial and complete responses.

  1. AT13387 in Treating Patients With Relapsed or Refractory Anaplastic Large Cell Lymphoma, Mantle Cell Lymphoma, or Diffuse Large B-cell Lymphoma

    ClinicalTrials.gov

    2017-04-04

    Anaplastic Large Cell Lymphoma, ALK-Positive; BCL6 Positive; Recurrent Anaplastic Large Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Anaplastic Large Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mantle Cell Lymphoma

  2. The Impact of Multiple AIDS-Related Bereavement in the Gay Male Population.

    ERIC Educational Resources Information Center

    Springer, Carrie A.; Lease, Suzanne H.

    2000-01-01

    Discusses the issue of AIDS-related loss and the correlative epidemic of AIDS-related bereavement. Notes that individuals are considered particularly susceptible to such bereavement when loss is multiple, as is often the case in the gay male population. Reviews the research exploring the impact of AIDS-related loss and suggests counseling…

  3. Relationship between pretreatment FDG-PET and diffusion-weighted MRI biomarkers in diffuse large B-cell lymphoma

    PubMed Central

    de Jong, Antoinette; Kwee, Thomas C; de Klerk, John MH; Adam, Judit A; de Keizer, Bart; Fijnheer, Rob; Kersten, Marie José; Ludwig, Inge; Jauw, Yvonne WS; Zijlstra, Josée M; den Bos, Indra C Pieters - Van; Stoker, Jaap; Hoekstra, Otto S; Nievelstein, Rutger AJ

    2014-01-01

    The purpose of this study was to determine the correlation between the 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) standardized uptake value (SUV) and the diffusion-weighted magnetic resonance imaging (MRI) apparent diffusion coefficient (ADC) in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Pretreatment FDG-PET and diffusion-weighted MRI of 21 patients with histologically proven DLBCL were prospectively analyzed. In each patient, maximum, mean and peak standardized uptake value (SUV) was measured in the lesion with visually highest FDG uptake and in the largest lesion. Mean ADC (ADCmean, calculated with b-values of 0 and 1000 s/mm2) was measured in the same lesions. Correlations between FDG-PET metrics (SUVmax, SUVmean, SUVpeak) and ADCmean were assessed using Pearson’s correlation coefficients. In the lesions with visually highest FDG uptake, no significant correlations were found between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.498, P=0.609 and P=0.595, respectively). In the largest lesions, there were no significant correlations either between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.992, P=0.843 and P=0.894, respectively). The results of this study indicate that the glycolytic rate as measured by FDG-PET and changes in water compartmentalization and water diffusion as measured by the ADC are independent biological phenomena in newly diagnosed DLBCL. Further studies are warranted to assess the complementary roles of these different imaging biomarkers in the evaluation and follow-up of DLBCL. PMID:24795837

  4. On molecular transport effects in real gas laminar diffusion flames at large pressure

    NASA Astrophysics Data System (ADS)

    Palle, Sridhar; Nolan, Christopher; Miller, Richard S.

    2005-10-01

    Direct numerical simulations are conducted of unsteady, exothermic and one-dimensional laminar diffusion flames at large pressures. The simulations are used to assess the impact of molecular diffusion and real gas effects under high pressure conditions with simplified chemical kinetics. The formulation includes the fully compressible form of the governing equations, real gas effects modeled by the cubic Peng-Robinson equation of state, and a generalized form of the Soret and Dufour mass and heat diffusion vectors derived from nonequilibrium thermodynamics and fluctuation theory. The cross diffusion fluxes are derived for a ternary species system and include the effects of both heat and mass diffusion in the presence of temperature, concentration and pressure gradients (i.e., Soret and Dufour diffusion). The ternary species formulation is applied to a simplified single step reaction elucidating molecular and thermodynamic effects apparent in general combustion. Realistic models for pressure, temperature and species dependent heat capacities, viscosities, thermal conductivities and mass diffusivities are also included. Three different model reactions are simulated both including and neglecting Soret and Dufour cross diffusion. The simulation results show that Soret and Dufour effects are negligible for reactions comprised of species with equal or near equal molecular weights. However, Soret diffusion effects are apparent when species with nonequal molecular weights are involved in the reaction and result in reductions of the peak flame temperature. In addition, it is shown that neglect of cross diffusion leads to deviations in the predicted flame thicknesses, with under predictions for a hydrogen-oxygen system and over predictions for a heavy hydrocarbon reaction. These effects are explained in detail through examinations of the individual heat and mass flux vectors as well as through associated thermodynamic properties. A parametric study addresses the effects of

  5. Long-term outcome of large artificial patch aortic repair for diffuse stenosis in Williams syndrome.

    PubMed

    Sughimoto, Koichi; Takahara, Yoshiharu; Mogi, Kenji; Sakurai, Manabu; Aoki, Chikashi

    2010-10-01

    There have been only a few reports concerning the long-term results of a surgical procedure using a large artificial patch for patients with Williams syndrome. Twelve years have passed since a patient with William's syndrome underwent a surgery with a patch angioplasty for the diffuse supravalvular aortic stenosis and deformities of the neck branch arteries. The patient had a well-balanced aortic growth without stenotic or aneurysmal changes, which was confirmed during the time of the second surgery when replacing the mitral valve. This technique of using a large patch has proven to be safe for Williams syndrome patients with diffuse supravalvular aortic stenosis in the long term.

  6. Single-relaxation-time lattice Boltzmann scheme for advection-diffusion problems with large diffusion-coefficient heterogeneities and high-advection transport.

    PubMed

    Perko, Janez; Patel, Ravi A

    2014-05-01

    The paper presents an approach that extends the flexibility of the standard lattice Boltzmann single relaxation time scheme in terms of spatial variation of dissipative terms (e.g., diffusion coefficient) and stability for high Péclet mass transfer problems. Spatial variability of diffusion coefficient in SRT is typically accommodated through the variation of relaxation time during the collision step. This method is effective but cannot deal with large diffusion coefficient variations, which can span over several orders of magnitude in some natural systems. The approach explores an alternative way of dealing with large diffusion coefficient variations in advection-diffusion transport systems by introducing so-called diffusion velocity. The diffusion velocity is essentially an additional convective term that replaces variations in diffusion coefficients vis-à-vis a chosen reference diffusion coefficient which defines the simulation time step. Special attention is paid to the main idea behind the diffusion velocity formulation and its implementation into the lattice Boltzmann framework. Finally, the performance, stability, and accuracy of the diffusion velocity formulation are discussed via several advection-diffusion transport benchmark examples. These examples demonstrate improved stability and flexibility of the proposed scheme with marginal consequences on the numerical performance.

  7. An experimental investigation of two large annular diffusers with swirling and distorted inflow

    NASA Technical Reports Server (NTRS)

    Eckert, W. T.; Johnston, J. P.; Simons, T. D.; Mort, K. W.; Page, V. R.

    1980-01-01

    Two annular diffusers downstream of a nacelle-mounted fan were tested for aerodynamic performance, measured in terms of two static pressure recovery parameters (one near the diffuser exit plane and one about three diameters downstream in the settling duct) in the presence of several inflow conditions. The two diffusers each had an inlet diameter of 1.84 m, an area ratio of 2.3, and an equivalent cone angle of 11.5, but were distinguished by centerbodies of different lengths. The dependence of diffuser performance on various combinations of swirling, radially distorted, and/or azimuthally distorted inflow was examined. Swirling flow and distortions in the axial velocity profile in the annulus upstream of the diffuser inlet were caused by the intrinsic flow patterns downstream of a fan in a duct and by artificial intensification of the distortions. Azimuthal distortions or defects were generated by the addition of four artificial devices (screens and fences). Pressure recovery data indicated beneficial effects of both radial distortion (for a limited range of distortion levels) and inflow swirl. Small amounts of azimuthal distortion created by the artificial devices produced only small effects on diffuser performance. A large artificial distortion device was required to produce enough azimuthal flow distortion to significantly degrade the diffuser static pressure recovery.

  8. Large interface diffusion in endotaxial growth of MnP films on GaP substrates

    SciTech Connect

    Nateghi, N. Ménard, D.; Masut, R. A.

    2014-10-07

    The metal organic vapor deposition of MnP films on GaP (100) substrates is shown to have a substantial endotaxial component. A study of the growth time evolution of the endotaxial depths of MnP grains reveals a diffusion-controlled growth with a relatively large diffusion coefficient of Mn in GaP. The value (2.2 ± 1.5) × 10⁻¹⁵ (cm²/s) obtained at 650 °C is at least two orders of magnitude larger than the reported Mn diffusion in bulk GaP. GaP surface mounds provide further indirect evidence that this large diffusion coefficient is concurrent with the out-diffusion of Ga atoms at the growing MnP/GaP interface. No trace of dislocations could be observed at or near this interface, which strongly suggests that Mn diffusion occurs through vacant sites generated by the difference between the crystallographic structures of MnP and GaP.

  9. Diffusion-limited attachment of large spherical particles to flexible membrane-immobilized receptors.

    PubMed

    Zhdanov, Vladimir P; Höök, Fredrik

    2015-05-01

    Relatively large (~100 nm) spherical particles, e.g., virions, vesicles, or metal nanoparticles, often interact with short (<10 nm) flexible receptors immobilized in a lipid membrane or on other biologically relevant surfaces. The attachment kinetics of such particles may be limited globally by their diffusion toward a membrane or locally by diffusion around receptors. The detachment kinetics, also, can be limited by diffusion. Focusing on local diffusion limitations and using suitable approximations, we present expressions for the corresponding rate constants and identify their dependence on particle size and receptor length. We also illustrate features likely to be observed in such kinetics for particles (e.g., vesicles) with a substantial size distribution. The results obtained are generic and can be used to interpret a variety of situations. For example, we estimate upper values of virion attachment rate constants and clarify the likely effect of vesicle size distribution on previously observed non-exponential kinetics of vesicle detachment.

  10. Direct Molecular Simulation of Gradient-Driven Diffusion of Large Molecules using Constant Pressure

    SciTech Connect

    Heffelfinger, G.S.; Thompson, A.P.

    1998-12-23

    Dual control volume grand canonical molecular dynamics (DCV-GCMD) is a boundary-driven non-equilibrium molecular dynamics technique for simulating gradient driven diffusion in multi-component systems. Two control volumes are established at opposite ends of the simulation box. Constant temperature and chemical potential of diffusing species are imposed in the control volumes. This results in stable chemical potential gradients and steady-state diffusion fluxes in the region between the control volumes. We present results and detailed analysis for a new constant-pressure variant of the DCV-GCMD method in which one of the diffusing species for which a steady-state diffusion flux exists does not have to be inserted or deIeted. Constant temperature, pressure and chemical potential of all diffusing species except one are imposed in the control volumes. The constant-pressure method can be applied to situations in which insertion and deletion of large molecules would be prohibitively difficult. As an exampIe, we used the method to shnulate diffusion in a biruuy mixture of spherical particles with a 2:1 size ratio. Steady-state diffusion fluxes of both diffbsi.ng species were established. The constant-pressure diffision coefficients agreed closely with the results of the standard constant-volume calculations. In addition, we show how the concentration, chemical potential and flux profiles can be used to calculate kwd binary and Maxwell-Stefim diffusion coefficients. In the case of the 2:1 size ratio mixture, we found that the binary dlffision coefficients were asymmetric and composition dependent, whereas the Maxwell-Stefan diffision coefficients changed very little with composition and were symmetric. This last result verified that the Gibbs-Duhem relation was satisfied locally, thus validating the assumption of local equilibrium.

  11. Detection of polyomavirus simian virus 40 tumor antigen DNA in AIDS-related systemic non-Hodgkin lymphoma

    NASA Technical Reports Server (NTRS)

    Vilchez, Regis A.; Lednicky, John A.; Halvorson, Steven J.; White, Zoe S.; Kozinetz, Claudia A.; Butel, Janet S.

    2002-01-01

    Systemic non-Hodgkin lymphoma (S-NHL) is a common malignancy during HIV infection, and it is hypothesized that infectious agents may be involved in the etiology. Epstein-Barr virus DNA is found in <40% of patients with AIDS-related S-NHL, suggesting that other oncogenic viruses, such as polyomaviruses, may play a role in pathogenesis. We analyzed AIDS-related S-NHL samples, NHL samples from HIV-negative patients, peripheral blood leukocytes from HIV-infected and -uninfected patients without NHL, and lymph nodes without tumors from HIV-infected patients. Specimens were examined by polymerase chain reaction analysis with use of primers specific for an N-terminal region of the oncoprotein large tumor antigen ( T-ag ) gene conserved among all three polyomaviruses (simian virus 40 [SV40], JC virus, and BK virus). Polyomavirus T-ag DNA sequences, proven to be SV40-specific, were detected more frequently in AIDS-related S-NHL samples (6 of 26) than in peripheral blood leukocytes from HIV-infected patients (6 of 26 vs. 0 of 69; p =.0001), NHL samples from HIV-negative patients (6 of 26 vs. 0 of 10; p =.09), or lymph nodes (6 of 26 vs. 0 of 7; p =.16). Sequences of C-terminal T-ag DNA from SV40 were amplified from two AIDS-related S-NHL samples. Epstein-Barr virus DNA sequences were detected in 38% (10 of 26) AIDS-related S-NHL samples, 50% (5 of 10) HIV-negative S-NHL samples, and 57% (4 of 7) lymph nodes. None of the S-NHL samples were positive for both Epstein-Barr virus DNA and SV40 DNA. Further studies of the possible role of SV40 in the pathogenesis of S-NHL are warranted.

  12. Cytomegalovirus enterocolitis in a patient with diffuse large B-cell lymphoma after chemotherapy with rituximab.

    PubMed

    Seewoodhary, Jason

    2006-12-07

    Rituximab has been associated with the development of cytomegalovirus enterocolitis in immunosuppressed patients. A 51-year-old patient with diffuse large B-cell lymphoma who received a conditioning chemotherapy regimen (RCVP and RICE) consisting of rituximab before bone marrow transplantation went on to develop cytomegalovirus enterocolitis. This supports evidence from previously described cases that rituximab may be associated with cytomegalovirus enterocolitis.

  13. Comparison of diffuse infrared and far-ultraviolet emission in the Large Magellanic Cloud: The data

    NASA Astrophysics Data System (ADS)

    Saikia, Gautam; Shalima, P.; Gogoi, Rupjyoti; Pathak, Amit

    2016-11-01

    Dust scattering is the main source of diffuse emission in the far-ultraviolet (FUV). For several locations in the Large Magellanic Cloud (LMC), Far Ultraviolet Spectroscopic Explorer (FUSE) satellite has observed diffuse radiation in the FUV with intensities ranging from 1000 to 3×105 photon units and diffuse fraction between 5% and 20% at 1100 Å. Here, we compare the FUV diffuse emission with the mid-infrared (MIR) and far-infrared (FIR) diffuse emission observed by the Spitzer Space Telescope and the AKARI satellite for the same locations. The intensity ratios in the different MIR and FIR bands for each of the locations will enable us to determine the type of dust contributing to the diffuse emission as well as to derive a more accurate 3D distribution of stars and dust in the region, which in turn may be used to model the observed scattering in the FUV. In this work we present the infrared (IR) data for two different regions in LMC, namely N11 and 30 Doradus. We also present the FUV IR correlation for different infrared bands.

  14. THEMIS Observations of the Magnetopause Electron Diffusion Region: Large Amplitude Waves and Heated Electrons

    NASA Technical Reports Server (NTRS)

    Tang, Xiangwei; Cattell, Cynthia; Dombeck, John; Dai, Lei; Wilson, Lynn B. III; Breneman, Aaron; Hupack, Adam

    2013-01-01

    We present the first observations of large amplitude waves in a well-defined electron diffusion region based on the criteria described by Scudder et al at the subsolar magnetopause using data from one Time History of Events and Macroscale Interactions during Substorms (THEMIS) satellite. These waves identified as whistler mode waves, electrostatic solitary waves, lower hybrid waves, and electrostatic electron cyclotron waves, are observed in the same 12 s waveform capture and in association with signatures of active magnetic reconnection. The large amplitude waves in the electron diffusion region are coincident with abrupt increases in electron parallel temperature suggesting strong wave heating. The whistler mode waves, which are at the electron scale and which enable us to probe electron dynamics in the diffusion region were analyzed in detail. The energetic electrons (approx. 30 keV) within the electron diffusion region have anisotropic distributions with T(sub e(right angle))/T(sub e(parallel)) > 1 that may provide the free energy for the whistler mode waves. The energetic anisotropic electrons may be produced during the reconnection process. The whistler mode waves propagate away from the center of the "X-line" along magnetic field lines, suggesting that the electron diffusion region is a possible source region of the whistler mode waves.

  15. Pathophysiology and molecular aspects of diffuse large B-cell lymphoma

    PubMed Central

    Gouveia, Gisele Rodrigues; Siqueira, Sheila Aparecida Coelho; Pereira, Juliana

    2012-01-01

    Diffuse large B-Cell lymphoma is the most common subtype of non-Hodgkin lymphoma in the West. In Brazil, it is the fifth cause of cancer, with more than 55,000 cases and 26,000 deaths per year. At Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - HCFMUSP, diffuse large B-Cell lymphoma represents 49.7% of all non-Hodgkin lymphoma cases. Initially, the classification of non-Hodgkin lymphoma was based on morphology, but advances in immunology and molecular medicine allowed the introduction of a biological classification for these diseases. As for other cancers, non-Hodgkin lymphoma involves patterns of multifactorial pathogenesis with environmental factors, as well as genetic, occupational and dietary factors, contributing to its development. Multiple lesions involving molecular pathways of B-cell proliferation and differentiation may result in the activation of oncogenes such as the BCL2, BCL6, and MYC genes and the inactivation of tumor suppressor genes such as p53 and INK4, as well as other important transcription factors such as OCT-1 and OCT-2. A dramatic improvement in survival was seen after the recent introduction of the anti-CD20 monoclonal antibody. The association of this antibody to the cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone (CHOP) regimen has increased overall survival of diffuse large B-Cell lymphoma and follicular lymphoma patients by 20%. However, 50% of all diffuse large B-Cell lymphoma patients remain incurable, creating a demand for more research with new advances in treatment. Thus, it is important to know and understand the key factors and molecular pathways involved in the pathogenesis of diffuse large B-Cell lymphoma. PMID:23323070

  16. High throughput tissue microarray analysis of FHIT expression in diffuse large cell B-cell lymphoma from Saudi Arabia.

    PubMed

    Al Kuraya, Khawla; Siraj, Abdul Khalid; Bavi, Prashant; Al-Jomah, Naif; El-Solh, Hassan; Ezzat, Adnan; Al-Dayel, Fouad; Belgaumi, Asim; Al-Kofide, Amani; Sabbah, Rajeh; Sheikh, Salwa; Amr, Samir; Simon, Ronald; Sauter, Guido

    2006-08-01

    Recent studies have suggested a potential prognostic role of alterations of the fragile histidine triad (FHIT) gene in diffuse large B-cell lymphoma. To evaluate possible mechanisms of FHIT inactivation and to further clarify its potential prognostic relevance, we analyzed a set of 114 diffuse large B-cell lymphoma with clinical follow-up information. Tissue microarrays were analyzed by immunohistochemistry for protein expression, and corresponding DNA samples were analyzed for FHIT promotor hypermethlyation. Reduced or absent FHIT expression was found in 75 of 114 diffuse large B-cell lymphoma (66%), but was unrelated to clinical tumor stage or patient prognosis. FHIT promotor hypermethylation was observed in 29 of 93 (23%) interpretable diffuse large B-cell lymphoma. Hypermethylation was not significantly correlated to protein expression loss, which could be explained by competing mechanisms for FHIT inactivation in a substantial fraction of non FHIT hypermethylated diffuse large B-cell lymphoma. Hypermethylation was significantly associated with poor prognosis of diffuse large B-cell lymphoma patients and predominantly seen in nongerminal center diffuse large B-cell lymphoma (27%), but less frequent (13%) in germinal center diffuse large B-cell lymphoma. In summary, these data suggest that promotor hypermethylation is responsible for reduced FHIT expression in a substantial subset of diffuse large B-cell lymphoma, which is primarily composed of nongerminal center subtype with poor patient prognosis.

  17. Diffuse large B-cell lymphoma, not otherwise specified of the palate: A case report

    PubMed Central

    Pereira, Thaís SF.; Castro, Alexandre F.; Mesquita, Ricardo A.

    2013-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of non-Hodgkin´s lymphoma found in oral and maxillofacial regions. A large number of cases may be biologically heterogeneous, which are commonly defined as DLBCL, not otherwise specified (NOS) by the World Health Organization (WHO-2008). The present case reports on an ulcer of raised and irregular edges, found on the border between the hard and soft palate, as the first and only manifestation of an extranodal non-Hodgkin lymphoma in an 85-year-old patient. Incisional biopsy was carried out, and the specimen revealed a proliferation of large lymphoid cells suggestive of diffuse large cell lymphoma. An immunohistochemical analysis was performed. EBV-RNA was assessed by in situ hybridization that also proved to be negative. Immunohistochemical and EBV analyses are important to avoid delays and inappropriate treatment strategies. Although advanced age is considered an adverse prognostic factor, early diagnosis did prove to be a key contributory factor in the cure of non-Hodgkin lymphoma. Key words:Diffuse large B-cell lymphoma, elderly, EBV. PMID:24455096

  18. Jump rates for surface diffusion of large molecules from first principles

    SciTech Connect

    Shea, Patrick Kreuzer, Hans Jürgen

    2015-04-21

    We apply a recently developed stochastic model for the surface diffusion of large molecules to calculate jump rates for 9,10-dithioanthracene on a Cu(111) surface. The necessary input parameters for the stochastic model are calculated from first principles using density functional theory (DFT). We find that the inclusion of van der Waals corrections to the DFT energies is critical to obtain good agreement with experimental results for the adsorption geometry and energy barrier for diffusion. The predictions for jump rates in our model are in excellent agreement with measured values and show a marked improvement over transition state theory (TST). We find that the jump rate prefactor is reduced by an order of magnitude from the TST estimate due to frictional damping resulting from energy exchange with surface phonons, as well as a rotational mode of the diffusing molecule.

  19. Intravenous Chemotherapy or Oral Chemotherapy in Treating Patients With Previously Untreated Stage III-IV HIV-Associated Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-09-29

    AIDS-related Diffuse Large Cell Lymphoma; AIDS-related Diffuse Mixed Cell Lymphoma; AIDS-related Diffuse Small Cleaved Cell Lymphoma; AIDS-related Immunoblastic Large Cell Lymphoma; AIDS-related Lymphoblastic Lymphoma; AIDS-related Peripheral/Systemic Lymphoma; AIDS-related Small Noncleaved Cell Lymphoma; Stage III AIDS-related Lymphoma; Stage IV AIDS-related Lymphoma

  20. Primary diffuse large B-cell lymphoma of the seminal vesicles: ultrasonography and computed tomography findings.

    PubMed

    Zhu, Jiang; Chen, Li-rong; Zhang, Xu; Gong, Yu; Xu, Jing-hong; Zheng, Shu

    2011-11-01

    Primary tumors of the seminal vesicle are very rare. We reported a 35-year-old man with a rare primary diffuse large B-cell lymphoma of the seminal vesicles. By transrectal ultrasound (TRUS) imaging, ultrasonic elastography (UE), and computed tomography (CT) imaging, the tumor was defined to locate in seminal vesicles. By TRUS-guided biopsy and histopathological examinations, the patient was diagnosed with large B-cell lymphoma. To our knowledge, this finding has not been reported before. We present the ultrasound and CT appearances of a case of large B-cell lymphoma of the seminal vesicles.

  1. Project of a Large Superconductor Detector Involving Directed Diffusion of Hot Electrons and Microcalorimeter

    SciTech Connect

    Shpinel, V.S.

    2005-12-01

    In recent years, radically new detectors for soft x rays and gamma rays were developed on the basis of superconducting tunnel junctions. These detectors made it possible to attain a very high resolution, but their largest area is overly small for employing them in nuclear spectroscopy. This study is devoted to the problem of designing a superconductor detector whose dimensions are sufficiently large for detecting gamma rays and which is suitable for applications in various fields of science. The detector consists of three units: an absorber, a hot-electron calorimeter, and a tunnel-junction (normal metal-insulator-superconductor) thermometer. The absorber has a multilayer structure consisting of thin superconductor layers arranged in the order of variation of the superconductor energy gap. This structure specifies the direction of hot-electron diffusion. Since quasiparticles diffuse in a specific direction, the diffusion time becomes shorter than that in the case of conventional diffusion. It is necessary that this time be shorter than the time of electron-phonon interaction. Calculations of the diffusion time for the particular structure in question and data from the literature on electron-phonon interaction show that the operating area of the detector can be about 3 to 4 mm{sup 2} and that its thickness can be about 1 mm. These dimensions can be considerably increased in the case of especially pure superconductors.

  2. A Case of p63 Positive Diffuse Large B Cell Lymphoma of the Bladder

    PubMed Central

    Jones, Carol

    2016-01-01

    Diffuse large B cell lymphoma (DLBCL), currently the most common type of non-Hodgkin lymphoma (NHL), is an aggressive B cell neoplasm that typically presents in older adults as a rapidly enlarging mass. The enlarging mass typically represents a lymph node, although extranodal disease can occur in a significant percentage (40%) of cases. The most common extranodal sites of involvement include the gastrointestinal tract and skin; primary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas. We report a case of diffuse large B cell lymphoma occurring in the bladder of an 83-year-old gentleman with an initial presentation of hematuria. This neoplasm displayed large, atypical cells with vesicular chromatin and prominent nucleoli that involved the bladder mucosa with invasion into muscularis propria, prostate, and urethra. Positive staining for p63 initially raised suspicion for poorly differentiated urothelial carcinoma; however, lack of staining for pancytokeratin and positive staining for LCA, CD20, CD79a, and PAX-5 confirmed the diagnosis of diffuse large B cell lymphoma. Though it does not occur in all cases, p63 can be positive in a significant percentage of cases of DLBCL; therefore, a diagnosis of lymphoma remains an important entity on the differential diagnosis of aggressive and particularly poorly differentiated neoplasms. PMID:27648316

  3. Diffuse large B-cell lymphoma of stomach presenting with paraneoplastic cerebellar degeneration syndrome.

    PubMed

    Nomani, Ali Zohair; Wazir, Marina; Kashmir, Saba Binte; Qureshi, Muhammad Saleem

    2014-03-01

    Paraneoplastic syndromes are most often diagnosed in the setting of a known malignancy. It is not uncommon for a paraneoplastic disorder to develop before a cancer is identified. While syndrome of cerebellar degeneration has been identified as a paraneoplastic manifestation of Hodgkin's lymphoma, thymoma, lung and breast cancer, ovarian and testicular tumors, melanoma, renal cell carcinoma, follicular lymphoma and adenocarcinoma of stomach, its association with non-Hodgkin's lymphoma and particularly diffuse large B-cell lymphoma has not been established previously. This case report describes the primary presentation with signs of paraneoplastic cerebellar degeneration as the only manifestation of an underlying diffuse large B-cell lymphoma making it the first of its kind to be formally reported. Furthermore, it also includes the identification of associated paraneoplastic antibodies for this particular syndrome.

  4. Coexistent Nodal Diffuse Large B-Cell Lymphoma With Extrapulmonary Tuberculosis: A Rare Case.

    PubMed

    Sachdev, Ritesh; Duggal, Rajan; Agrawal, Krati; Goel, Shalini

    2016-02-01

    Extrapulmonary tuberculosis coexistent with lymphomas in the same organ are rare and have been reported in the literature. The most common organs that are involved are small bowel, bronchus, kidney, and lymph nodes. Interestingly, the lymphoma that is commonly present with extrapulmonary tuberculosis is Hodgkin's lymphoma followed by low-grade non-Hodgkin's lymphoma. In the present study, we report a 60-year-old man with complaints of fever, loss of appetite, and generalized weakness. On investigation, generalized lymphadenopathy was noted, and the biopsy of cervical lymph node revealed coexistence of diffuse large B-cell lymphoma with extrapulmonary tuberculosis. This case is the second reported case of diffuse large B-cell lymphoma with extrapulmonary tuberculosis in the world and the first in India.

  5. Measuring HIV/AIDS-Related Stigma across South Africa: A Versatile and Multidimensional Scale

    ERIC Educational Resources Information Center

    Smith, Edward A.; Miller, Jacqueline A.; Newsome, Valerie; Sofolahan, Yewande A.; Airhihenbuwa, Collins O.

    2014-01-01

    Reducing HIV/AIDS-related stigma is critical in the fight against HIV/AIDS. Although national campaigns and prevention programs have been implemented across South Africa to address this critical concern, assessing the impact of these initiatives is difficult as it requires that measurement of HIV/AIDS-related stigma is uniform and comparable…

  6. Time-to-treatment of diffuse large B-cell lymphoma in São Paulo

    PubMed Central

    Xavier, Flávia Dias; Levy, Debora; Pereira, Juliana

    2014-01-01

    OBJECTIVE: Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma, accounting for nearly 50% of the cases in the Hematology Department of the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo. The treatment outcome is influenced by age, abnormal lactate dehydrogenase levels, extranodal infiltration, the disease stage and the patient's performance status. In this study, we sought to report the time-to-treatment of diffuse large B-cell lymphoma in São Paulo's public health system network and its impact on patient outcomes. METHODS: We prospectively followed a cohort of 42 consecutive patients with de novo diffuse large B-cell lymphoma between 2008 and 2012. RESULTS: Our patients had more advanced disease than that reported in the literature (61.9% vs. 46%). In São Paulo's public health system network, it took an average of 7.4 months for a diagnosis to be made and an additional 1.4 months to obtain an appointment with a specialist. Once at our Hematology Department, it took less than 20 days for staging, confirmation of the diagnosis and treatment initiation. An interval from signs or symptoms to treatment of more than 6 months was associated with inferior progression-free survival in 3 years (p = 0.049). CONCLUSION: A delay in the diagnosis of diffuse large B-cell lymphoma is a public health problem and may be associated with worse progression-free survival. PMID:24838904

  7. Diagnosis and treatment of diffuse large B-cell lymphoma in an orangutan (Pongo pygmaeus).

    PubMed

    Ikpatt, Offiong F; Reavill, Drury; Chatfield, Jason; Clubb, Susan; Rosenblatt, Joseph D; Fonte, Glenn; Fan, Yao-Shan; Cray, Carolyn

    2014-12-01

    Lymphoma is a common malignancy observed in companion animals. This type of naturally occurring neoplasia has been uncommonly reported in great apes. Diffuse large B-cell lymphoma was diagnosed in an 8-yr-old captive orangutan (Pongo pygmaeus) with gastrointestinal disease by histologic and immunohistochemical methodologies. The orangutan was treated with three cycles of combination chemotherapy (intravenous Rituxan, cyclophosphamide, doxorubicin, and vincristine). The primate has been in good health and exhibiting normal behaviors for more than 15 mo following treatment.

  8. Diffuse large B-cell lymphoma diagnosed by intracardiac echocardiography-guided cardiac tumor biopsy.

    PubMed

    Kamiya, Kiwamu; Sakakibara, Mamoru; Yamada, Shiro; Tan, Michinao; Furihata, Takaaki; Kubota, Kanako; Tsutsui, Hiroyuki

    2012-01-01

    A 44-year-old man presented with exertional dyspnea. Transthoracic echocardiography (TTE) revealed a large tumor protruding into the right atrium and extending into the left ventricle. Cardiac magnetic resonance imaging and contrast enhanced computed tomography also confirmed the intracardiac tumor detected by TTE. An endomyocardial biopsy was performed under the intracardiac echocardiography (ICE) guidance, and he was diagnosed to have diffuse large B-cell lymphoma following the histological analysis. ICE-guided cardiac tumor biopsy is expected to be a useful diagnostic strategy that can minimize the risk of procedural complications.

  9. Nuclear criticality safety evaluation of large cylinder cleaning operations in X-705, Portsmouth Gaseous diffusion Plant

    SciTech Connect

    Sheaffer, M.K.; Keeton, S.C.; Lutz, H.F.

    1995-06-01

    This report evaluates nuclear criticality safety for large cylinder cleaning operations in the Decontamination and Recovery Facility, X-705, at the Portsmouth Gaseous Diffusion Plant. A general description of current cleaning procedures and required hardware/equipment is presented, and documentation for large cylinder cleaning operations is identified and described. Control parameters, design features, administrative controls, and safety systems relevant to nuclear criticality are discussed individually, followed by an overall assessment based on the Double Contingency Principle. Recommendations for enhanced safety are suggested, and issues for increased efficiency are presented.

  10. Pityriasis lichenoids chronica as a paraneoplastic dermatosis for primary splenic diffuse large B cell lymphoma.

    PubMed

    Lu, Ying-Yi; Liao, Jia-Bin; Wu, Chieh-Shan; Hong, Chien-Hui

    2014-09-01

    Paraneoplastic dermatosis is defined as both benign skin lesions and internal malignancy existing at the same time with parallel clinical courses. Herein, we report a 91-year-old male who presented as pityriasis lichenoids chronica (PLC) concomitantly with a primary splenic diffuse large B cell lymphoma. Surgical removal of the spleen cleared his skin lesions dramatically. However, seven months later, the splenic lymphoma relapsed in concordance with the recurrence of the skin lesions of PLC. To our knowledge, he is the first case that PLC is the leading presentation and paraneoplastic manifestation of primary splenic large B-cell lymphoma.

  11. Fermi Large Area Telescope Measurements of the Diffuse Gamma-Ray Emission at Intermediate Galactic Latitudes

    SciTech Connect

    Abdo, A.A.; Ackermann, M.; Ajello, M.; Anderson, B.; Atwood, W.B.; Axelsson, M.; Baldini, L.; Ballet, J.; Barbiellini, G.; Bastieri, D.; Baughman, B.M.; Bechtol, K.; Bellazzini, R.; Berenji, B.; Blandford, R.D.; Bloom, E.D.; Bonamente, E.; Borgland, A.W.; Bregeon, J.; Brez, A.; Brigida, M.; /more authors..

    2012-04-11

    The diffuse galactic {gamma}-ray emission is produced by cosmic rays (CRs) interacting with the interstellar gas and radiation field. Measurements by the Energetic Gamma-Ray Experiment Telescope (EGRET) instrument on the Compton Gamma-Ray Observatory indicated excess {gamma}-ray emission {ge}1 GeV relative to diffuse galactic {gamma}-ray emission models consistent with directly measured CR spectra (the so-called 'EGRET GeV excess'). The Large Area Telescope (LAT) instrument on the Fermi Gamma-Ray Space Telescope has measured the diffuse {gamma}-ray emission with improved sensitivity and resolution compared to EGRET. We report on LAT measurements for energies 100 MeV to 10 GeV and galactic latitudes 10{sup o} {le} |b| {le} 20{sup o}. The LAT spectrum for this region of the sky is well reproduced by a diffuse galactic {gamma}-ray emission model that is consistent with local CR spectra and inconsistent with the EGRET GeV excess.

  12. Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting.

    PubMed

    Zhu, Charles; Sempkowski, Michelle; Holleran, Timothy; Linz, Thomas; Bertalan, Thomas; Josefsson, Anders; Bruchertseifer, Frank; Morgenstern, Alfred; Sofou, Stavroula

    2017-06-01

    Diffusion limitations on the penetration of nanocarriers in solid tumors hamper their therapeutic use when labeled with α-particle emitters. This is mostly due to the α-particles' relatively short range (≤100 μm) resulting in partial tumor irradiation and limited killing. To utilize the high therapeutic potential of α-particles against solid tumors, we designed non-targeted, non-internalizing nanometer-sized tunable carriers (pH-tunable liposomes) that are triggered to release, within the slightly acidic tumor interstitium, highly-diffusive forms of the encapsulated α-particle generator Actinium-225 ((225)Ac) resulting in more homogeneous distributions of the α-particle emitters, improving uniformity in tumor irradiation and increasing killing efficacies. On large multicellular spheroids (400 μm-in-diameter), used as surrogates of the avascular areas of solid tumors, interstitially-releasing liposomes resulted in best growth control independent of HER2 expression followed in performance by (a) the HER2-targeting radiolabeled antibody or (b) the non-responsive liposomes. In an orthotopic human HER2-negative mouse model, interstitially-releasing (225)Ac-loaded liposomes resulted in the longest overall and median survival. This study demonstrates the therapeutic potential of a general strategy to bypass the diffusion-limited transport of radionuclide carriers in solid tumors enabling interstitial release from non-internalizing nanocarriers of highly-diffusing and deeper tumor-penetrating molecular forms of α-particle emitters, independent of cell-targeting.

  13. Large-eddy simulation of flow through a plane, asymmetric diffuser

    NASA Technical Reports Server (NTRS)

    Kaltenbach, Hans-Jakob

    1994-01-01

    A challenge for traditional turbulence modeling, based on the Reynolds averaged Navier-Stokes equations, remains the accurate prediction of 'mild', adverse pressure-gradient driven separation from a smooth surface. With this study we want to explore the capability of large-eddy simulation to predict the separation which occurs on the deflected wall of an asymmetric, plane diffuser with opening angle of 10 deg. The flow through the plane diffuser exhibits some additional interesting physical phenomena which make it a challenging test case. In addition to 'mild' separation about halfway down the deflected ramp, the flow is characterized by a small backflow zone with stalled fluid in the rear part of the expanding section. The turbulent flow entering the diffuser is subject to combined adverse and radial pressure gradients stemming from the convex curvature. Finally the flow recovers into a developed, turbulent channel flow in the outlet section. Obi et al. provide measurements of mean flow, Reynolds stresses, and pressure recovery, which were obtained by means of LDV in a wind tunnel. The objective of this study is to investigate whether LES with the standard dynamic model is able to accurately predict the flow in the one-sided diffuser and to explore the resolution requirements and associated costs.

  14. Diffusion Dynamics of Energy Saving Practices in Large Heterogeneous Online Networks

    PubMed Central

    Mohammadi, Neda; Wang, Qi; Taylor, John E.

    2016-01-01

    Online social networks are today’s fastest growing communications channel and a popular source of information for many, so understanding their contribution to building awareness and shaping public perceptions of climate change is of utmost importance. Today’s online social networks are composed of complex combinations of entities and communication channels and it is not clear which communicators are the most influential, what the patterns of communication flow are, or even whether the widely accepted two-step flow of communication model applies in this new arena. This study examines the diffusion of energy saving practices in a large online social network across organizations, opinion leaders, and the public by tracking 108,771 communications on energy saving practices among 1,084 communicators, then analyzing the flow of information and influence over a 28 day period. Our findings suggest that diffusion networks of messages advocating energy saving practices are predominantly led by the activities of dedicated organizations but their attempts do not result in substantial public awareness, as most of these communications are effectively trapped in organizational loops in which messages are simply shared between organizations. Despite their comparably significant influential values, opinion leaders played a weak role in diffusing energy saving practices to a wider audience. Thus, the two-step flow of communication model does not appear to describe the sharing of energy conservation practices in large online heterogeneous networks. These results shed new light on the underlying mechanisms driving the diffusion of important societal issues such as energy efficiency, particularly in the context of large online social media outlets. PMID:27736912

  15. Diffusion Dynamics of Energy Saving Practices in Large Heterogeneous Online Networks.

    PubMed

    Mohammadi, Neda; Wang, Qi; Taylor, John E

    2016-01-01

    Online social networks are today's fastest growing communications channel and a popular source of information for many, so understanding their contribution to building awareness and shaping public perceptions of climate change is of utmost importance. Today's online social networks are composed of complex combinations of entities and communication channels and it is not clear which communicators are the most influential, what the patterns of communication flow are, or even whether the widely accepted two-step flow of communication model applies in this new arena. This study examines the diffusion of energy saving practices in a large online social network across organizations, opinion leaders, and the public by tracking 108,771 communications on energy saving practices among 1,084 communicators, then analyzing the flow of information and influence over a 28 day period. Our findings suggest that diffusion networks of messages advocating energy saving practices are predominantly led by the activities of dedicated organizations but their attempts do not result in substantial public awareness, as most of these communications are effectively trapped in organizational loops in which messages are simply shared between organizations. Despite their comparably significant influential values, opinion leaders played a weak role in diffusing energy saving practices to a wider audience. Thus, the two-step flow of communication model does not appear to describe the sharing of energy conservation practices in large online heterogeneous networks. These results shed new light on the underlying mechanisms driving the diffusion of important societal issues such as energy efficiency, particularly in the context of large online social media outlets.

  16. A case of diffuse large B-cell lymphoma misdiagnosed as an erysipelas of the face

    PubMed Central

    Szymańska, Magdalena; Czarnecka-Operacz, Magdalena

    2013-01-01

    We report a case of a woman with diffuse large B-cell lymphoma (DLBCL). Primary cutaneous lymphomas (PCLs) represent distinct clinical and histopathologic subtypes of extranodal T- and B-cell lymphomas. Cutaneous B-cell lymphomas comprise 20–25% of all primary cutaneous lymphomas. The patient presented an erythematous tumour mass of the left nasolabial fold, nose and left cheek as well as disseminated infiltrative plagues on the trunk, arms and left lower leg. Skin biopsy revealed a diffuse infiltrate of lymphocytes around hair follicles and blood vessels within dermis and subcutaneous tissue. An immunohistochemistry showed a diffuse infiltrate of large non-cleaved B-cells, with a high proportion of centroblast-like cells within dermis. Tumor cells expressed CD20, bcl-2 protein and did not express CD10. The patient was misdiagnosed as the erysipelas of the face and unsuccessfully treated with long-term antibiotic therapy by a laryngologist and a dermatologist. The correct diagnosis was delayed and established after 6 months’ history of DLBCL lesions. Therefore, we would like to strongly stress the importance of considering diagnosis of cutaneous lymphomas in chronic skin lesions non-responsive to adequate therapies. PMID:24278087

  17. Diffusion on complex networks: a way to probe their large-scale topological structures

    NASA Astrophysics Data System (ADS)

    Simonsen, Ingve; Astrup Eriksen, Kasper; Maslov, Sergei; Sneppen, Kim

    2004-05-01

    A diffusion process on complex networks is introduced in order to uncover their large-scale topological structures. This is achieved by focusing on the slowest decaying diffusive modes of the network. The proposed procedure is applied to real-world networks like a friendship network of known modular structure, and an Internet routing network. For the friendship network, its known structure is well reproduced. In case of the Internet, where the structure is far less well known, one indeed finds a modular structure, and modules can roughly be associated with individual countries. Quantitatively, the modular structure of the Internet manifests itself in an approximately 10 times larger participation ratio of its slowest decaying modes as compared to the null model-a random scale-free network. The extreme edges of the Internet are found to correspond to Russian and US military sites.

  18. Improved lattice Boltzmann model for multi-component diffusion flow with large pressure difference

    NASA Astrophysics Data System (ADS)

    Liu, Fu-Min; Wang, An-Lin; Qiu, Ruo-Fan; Jiang, Tao

    2016-05-01

    The pseudopotential lattice Boltzmann model has been widely used to solve multi-phase and multi-component flow problems. However, original pseudopotential model cannot be used in simulating diffusion flow with large pressure difference because of its limitation. In this paper, we incorporate pseudopotential model with a new form of effective mass to solve this problem based on the relationship between pressure difference and effective mass. The improved model is verified through Laplace’s law and binary immiscible Poiseuille flow. By simulating pipeline binary diffusion flow and two-inlet binary cavity jet flow, we show that the improved model can achieve larger pressure difference than pseudopotential model with traditional effective mass forms.

  19. Study of HIV/AIDS-related knowledge among junior high-school students in Shanghai, China.

    PubMed

    Cai, Y; Shi, R; Li, S; Xu, G; Huang, H

    2012-03-01

    The aim of this study was to assess the HIV/AIDS-related knowledge among junior high-school students in Shanghai, China, and the factors influencing this knowledge. A cross-sectional study was conducted in 20 middle schools of two districts by a cluster-stratified selection procedure in Shanghai, China. The 2432 sampled students, aged from 11.1 to 16.7 years, completed a self-administered questionnaire of HIV/AIDS prevention. The results showed that the overall correct rate of HIV/AIDS-related knowledge was 62%. Using multivariable logistic regression analysis, we found that the main factors influencing HIV/AIDS-related knowledge among junior high school students were the type of school (odds ratio [OR] = 1.641), age (OR = 1.727), whether the student was a single child in the family (OR = 1.389), whether the student had previous HIV/AIDS-related education experience (OR = 2.003) and whether the student had ever discussed HIV/AIDS with their parents (OR = 1.282). The results indicate that HIV/AIDS-related knowledge among Shanghai junior high school students is not high enough, and more attention needs to be paid to enhance HIV/AIDS-related knowledge, especially among younger students from common type schools without HIV/AIDS-related education experience. We encourage Chinese parents to get involved in their children's HIV/AIDS prevention education.

  20. Unusually Aggressive Primary Testicular Diffuse Large B Cell Lymphoma with Post Therapy Extensive Metastasis

    PubMed Central

    Goel, Shalini; Mohapatra, Ishani; Gajendra, Smeeta; Gupta, Sunil

    2016-01-01

    Primary Testicular Lymphoma (PTL) is a rare intermediate to high grade tumour, diffuse large cell being the most common type. Unlike nodal Diffuse Large B-Cell Lymphoma (DLBCL), testicular DLBCL has a less aggressive course and better prognosis. Metastasis is uncommon in testicular DLBCL. Commonly involved sites are contralateral testes, Waldeyer’s ring, skin, lung, Central Nervous System (CNS) and prostate, however the kidneys, liver, bone marrow, pleura and bones are more rarely involved. We report a case of testicular DLBCL which has metastasized to skin and bone marrow with an aggressive clinical course in a year, in-spite of combined modality of therapy given to the patient. Bone marrow infiltration is common and well documented with nodal DLBCL, however there is no published literature for simultaneous bone marrow and skin infiltration in testicular DLBCL till date. Other large studies done in the west have shown that distinct metastasis is usually common but the median progression-free survival is usually in years. This case stresses on shorter period of progression after standard treatment protocol in this part of the world, thus highlighting the need for other extensive studies to define specific treatment protocol for testicular DLBCL. PMID:27630854

  1. Interim PET Scans in Diffuse Large B-Cell Lymphoma: Is It Ready for Prime Time?

    PubMed

    Bolshinsky, Maital; Nabhan, Chadi

    2016-12-01

    Prognostication of patients with diffuse large B-cell lymphoma (DLBCL) has improved in the past decade with a variety of clinical, morphologic, molecular, and radiographic methods. Comparable to data on the value of interim positron emission tomography (I-PET) in Hodgkin lymphoma, several retrospective and prospective studies are attempting to assess the value of I-PET scanning in DLBCL patients. In this review, we briefly describe and analyze the various prognostic methods in DLBCL with specific focus on the value of I-PET scanning in this disease. This is a timely analysis, as tailoring therapies based on prognosis at diagnosis are becoming of increased investigational interest.

  2. Large-eddy simulation of flow in a plane, asymmetric diffuser

    NASA Technical Reports Server (NTRS)

    Kaltenbach, Hans-Jakob

    1993-01-01

    Recent improvements in subgrid-scale modeling as well as increases in computer power make it feasible to investigate flows using large-eddy simulation (LES) which have been traditionally studied with techniques based on Reynolds averaging. However, LES has not yet been applied to many flows of immediate technical interest. Preliminary results from LES of a plane diffuser flow are described. The long term goal of this work is to investigate flow separation as well as separation control in ducts and ramp-like geometries.

  3. Diffuse large B cell lymphoma presenting as a peri-anal abscess.

    PubMed

    Jayasekera, Hasanga; Gorissen, Kym; Francis, Leo; Chow, Carina

    2014-06-04

    A non-healing peri-anal abscess can be difficult to manage and is often attributed to chronic disease. This case documents a male in his seventh decade who presented with multiple peri-anal collections. The abscess cavity had caused necrosis of the internal sphincter muscles resulting in faecal incontinence. Biopsies were conclusive for diffuse large B-cell lymphoma. A de-functioning colostomy was performed and the patient was initiated on CHOP-R chemotherapy. Anal lymphoma masquerading as a peri-anal abscess is rare. A high degree of suspicion must be maintained for an anal abscess which does not resolve with conservative management.

  4. Highly transparent sapphire micro-grating structures with large diffuse light scattering.

    PubMed

    Ko, Yeong Hwan; Yu, Jae Su

    2011-08-01

    The highly transparent micro-grating structures (MGSs) of sapphire substrate with large diffuse light scattering were theoretically and experimentally studied. From the finite difference time domain simulation, it was found that the degree of diffuse light scattering is strongly dependent on the size of grating structures. For a highly transparent property, the sapphire MGSs were optimally designed by the theoretical calculations using the rigorous coupled wave analysis method. The order of taper, geometry (i.e., width and height), and pitch length of MGSs were optimized to maximize their average total transmittance over a wide wavelength range of 300-1800 nm. Additionally, the influence of the deposition of low-refractive index material such as SiO2 onto sapphire MGSs on the transmittance characteristics was investigated. To verify experimentally the feasibility, the sapphire MGSs were fabricated by the conventional lithography and dry etching processes. The SiO2 deposited sapphire MGS exhibited a further increase in the total transmittance due to its relatively more graded refractive index profile while maintaining a significantly enhanced diffuse light scattering. The experimental data were in a reasonable agreement with the theoretical results.

  5. Measurement of large spiral and target waves in chemical reaction-diffusion-advection systems: turbulent diffusion enhances pattern formation.

    PubMed

    von Kameke, A; Huhn, F; Muñuzuri, A P; Pérez-Muñuzuri, V

    2013-02-22

    In the absence of advection, reaction-diffusion systems are able to organize into spatiotemporal patterns, in particular spiral and target waves. Whenever advection is present that can be parametrized in terms of effective or turbulent diffusion D(*), these patterns should be attainable on a much greater, boosted length scale. However, so far, experimental evidence of these boosted patterns in a turbulent flow was lacking. Here, we report the first experimental observation of boosted target and spiral patterns in an excitable chemical reaction in a quasi-two-dimensional turbulent flow. The wave patterns observed are ~50 times larger than in the case of molecular diffusion only. We vary the turbulent diffusion coefficient D(*) of the flow and find that the fundamental Fisher-Kolmogorov-Petrovsky-Piskunov equation, v(f) proportional sqrt[D(*)], for the asymptotic speed of a reactive wave remains valid. However, not all measures of the boosted wave scale with D(*) as expected from molecular diffusion, since the wave fronts turn out to be highly filamentous.

  6. Large Eddy Simulation of Gravitational Effects on Transitional and Turbulent Gas-Jet Diffusion Flames

    NASA Technical Reports Server (NTRS)

    Givi, Peyman; Jaberi, Farhad A.

    2001-01-01

    The basic objective of this work is to assess the influence of gravity on "the compositional and the spatial structures" of transitional and turbulent diffusion flames via large eddy simulation (LES), and direct numerical simulation (DNS). The DNS is conducted for appraisal of the various closures employed in LES, and to study the effect of buoyancy on the small scale flow features. The LES is based on our "filtered mass density function"' (FMDF) model. The novelty of the methodology is that it allows for reliable simulations with inclusion of "realistic physics." It also allows for detailed analysis of the unsteady large scale flow evolution and compositional flame structure which is not usually possible via Reynolds averaged simulations.

  7. Emergence of large-scale vorticity during diffusion in a random potential under an alternating bias.

    PubMed

    Makeev, Maxim A; Derényi, Imre; Barabási, Albert-László

    2005-02-01

    Conventional wisdom indicates that the presence of an alternating driving force will not change the long-term behavior of a Brownian particle moving in a random potential. Although this is true in one dimension, here we offer direct evidence that the inevitable local symmetry breaking present in a two-dimensional random potential leads to the emergence of a local ratchet effect that generates large-scale vorticity patterns consisting of steady-state net diffusive currents. For small fields the spatial correlation function of the current follows a logarithmic distance dependence, while for large external fields both the vorticity and the correlations gradually disappear. We uncover the scaling laws characterizing this unique pattern formation process, and discuss their potential relevance to real systems.

  8. [Marfan syndrome complicated with CD5+ CD10+ diffuse large B-cell lymphoma].

    PubMed

    Yoshitake, Kumiko; Hagiwara, Yuki; Tanae, Ken; Takahashi, Naoki; Kohri, Mika; Tamaru, Jun-ichi; Bessho, Masami; Niitsu, Nozomi

    2010-03-01

    Marfan syndrome (MFS) is caused by mutations in the gene encoding fibrillin. A 35-year-old man with MFS visited a local physician because of a sore throat. His left tonsil gradually became swollen and he was referred to our department. Histopathological examination of tonsil biopsy specimens showed diffuse proliferation of lymphoma cells with large nuclei. The tumor cells showed CD5+, CD10+, CD20+, BCL-6+, and MUM-1-. Based on these findings, the patient was diagnosed with CD5+ CD10+ diffuse large B-cell lymphoma (DLBCL). Chemotherapy combined with rituximab was administered and complete response was achieved. CD5+ DLBCL comprises approximately 5 approximately 10% of DLBCLs. In addition, CD5+ CD10+ DLBCL comprises about 5% of CD5+ DLBCLs. There may be a relationship between MFS and B-cell lymphoma because mutations in the gene encoding the receptor of transforming growth factor-beta (TGF-beta) have been implicated in the pathogenesis of MFS and downregulation of TGF-beta receptor expression has been described in the pathology of B-cell lymphoma.

  9. MLL2 protein is a prognostic marker for gastrointestinal diffuse large B-cell lymphoma

    PubMed Central

    Ye, Haige; Lu, Lu; Ge, Bei; Gao, Shenmeng; Ma, Yongyong; Liang, Bin; Yu, Kang; Yang, Kaiyan

    2015-01-01

    Mixed linage leukemia gene 2 (MLL2) is identified as a novel mutation gene in diffuse large B cell lymphoma (DLBCL). However, the significance of MLL2 protein expression for the prognosis of DLBCL is unclear. In this study, we detected MLL2 protein expression in primary gastrointestinal diffuse large B cell lymphoma (PGI-DLBCL) samples by using tissue microarray immunohistochemistry, and analyzed the correlation between MLL2 protein expression and tumor proliferation activity. In addition, we investigated clinical significance of MLL2 protein expression for PGI-DLBCL prognosis. We found that there was significant difference in MLL2 protein expression between PGI-DLBCL and reactive hyperplasia of lymph node. High expression of MLL2 protein indicated higher clinical stage. In older patients (>60 years) with PGI-DLBCL, MLL2 protein expression was positively correlated with Ki-67 expression and negatively correlated with patient survival. Our data suggest that MLL2 protein is overexpressed in PGI-DLBCL and appears as a prognostic factor for patients of PGI-DLBCL, especially for those older than 60 years old. PMID:26722499

  10. Numerical investigation of high pressure and high Reynolds diffusion flame using Large Eddy Simulation

    NASA Astrophysics Data System (ADS)

    Nichkoohi, Ali Lohrasbi; Tousi, Abolghasem Mesgarpour

    2014-10-01

    Today, with nonstop improvement in computational power, Large-Eddy Simulation (LES) is a high demanding research tool for predicting engineering flows. Such flows on high pressure condition like diesel engines is extensively employed in ground and marine transportation, oblige the designer to control and predict toxic pollutants, while maintaining or improving their high thermal efficiency. This becomes one of the main challenging issues in decades. In the present work, numerical investigation of diffusion flame dynamics is performed in the near-field of high-Reynolds jet flow on high pressure condition encountered in diesel engine applications. This work discusses the implementation of Partially Stirred Reactor (PaSR) combustion model by the approaches of large eddy simulation (LES). The simulation results show that LES, in comparison with Reynolds-Averaged Navier-Stokes (RANS) simulation predicts and captures transient phenomena very well. These phenomena such as unsteadiness and curvature are inherent in the near-field of high Reynolds diffusion flame. The outcomes of this research are compared and validated by other researchers' results. Detailed comparisons of the statistics show good agreement with the corresponding experiments.

  11. AIDS-related Pneumocystis jirovecii genotypes in French Guiana.

    PubMed

    Le Gal, Solène; Blanchet, Denis; Damiani, Céline; Guéguen, Paul; Virmaux, Michèle; Abboud, Philippe; Guillot, Geneviève; Kérangart, Stéphane; Merle, Cédric; Calderon, Enrique; Totet, Anne; Carme, Bernard; Nevez, Gilles

    2015-01-01

    The study described Pneumocystis jirovecii (P. jirovecii) multilocus typing in seven AIDS patients living in French Guiana (Cayenne Hospital) and seven immunosuppressed patients living in Brest, metropolitan France (Brest Hospital). Archival P. jirovecii specimens were examined at the dihydropteroate synthase (DHPS) locus using a PCR-RFLP technique, the internal transcribed spacer (ITS) 1 and ITS 2 and the mitochondrial large subunit rRNA (mtLSUrRNA) gene using PCR and sequencing. Analysis of typing results were combined with an analysis of the literature on P. jirovecii mtLSUrRNA types and ITS haplotypes. A wild DHPS type was identified in six Guianese patients and in seven patients from metropolitan France whereas a DHPS mutant was infected in the remaining Guianese patient. Typing of the two other loci pointed out a high diversity of ITS haplotypes and an average diversity of mtLSUrRNA types in French Guiana with a partial commonality of these haplotypes and types described in metropolitan France and around the world. Combining DHPS, ITS and mtLSU types, 12 different multilocus genotypes (MLGs) were identified, 4 MLGs in Guianese patients and 8 MLGs in Brest patients. MLG analysis allows to discriminate patients in 2 groups according to their geographical origin. Indeed, none of the MLGs identified in the Guianese patients were found in the Brest patients and none of the MLGs identified in the Brest patients were found in the Guianese patients. These results show that in French Guiana (i) PCP involving DHPS mutants occur, (ii) there is a diversity of ITS and mtLSUrRNA types and (iii) although partial type commonality in this territory and metropolitan France can be observed, MLG analysis suggests that P. jirovecii organisms from French Guiana may present specific characteristics.

  12. Uncovering Implicit Assumptions: a Large-Scale Study on Students' Mental Models of Diffusion

    NASA Astrophysics Data System (ADS)

    Stains, Marilyne; Sevian, Hannah

    2015-12-01

    Students' mental models of diffusion in a gas phase solution were studied through the use of the Structure and Motion of Matter (SAMM) survey. This survey permits identification of categories of ways students think about the structure of the gaseous solute and solvent, the origin of motion of gas particles, and trajectories of solute particles in the gaseous medium. A large sample of data ( N = 423) from students across grade 8 (age 13) through upper-level undergraduate was subjected to a cluster analysis to determine the main mental models present. The cluster analysis resulted in a reduced data set ( N = 308), and then, mental models were ascertained from robust clusters. The mental models that emerged from analysis were triangulated through interview data and characterised according to underlying implicit assumptions that guide and constrain thinking about diffusion of a solute in a gaseous medium. Impacts of students' level of preparation in science and relationships of mental models to science disciplines studied by students were examined. Implications are discussed for the value of this approach to identify typical mental models and the sets of implicit assumptions that constrain them.

  13. Cooling following large volcanic eruptions corrected for the effect of diffuse radiation on tree rings

    NASA Astrophysics Data System (ADS)

    Robock, Alan

    2005-03-01

    The lack of a larger cooling in proxy records of climate change following large volcanic eruptions such as those of Tambora in 1815 and Krakatau in 1883 has long been a puzzle for climatologists. These records, however, may have been biased by enhanced tree growth for several years following each eruption induced by additional diffuse radiation caused by the stratospheric volcanic aerosol clouds from the eruptions. By comparing proxy reconstructions of climate with and without tree ring data, this effect is demonstrated for the five largest eruptions for the period 1750-1980. When proxy records of Northern Hemisphere climate change are corrected for this proposed diffuse effect, there is no impact on climate change for time scales longer than 20 years. However, it now appears that there was a hemispheric cooling of about 0.6°C for a decade following the unknown volcanic eruption of 1809 and Tambora in 1815, and a cooling of 0.3°C for several years following the Krakatau eruption of 1883.

  14. Laser soot-scattering imaging of a large buoyant diffusion flame

    SciTech Connect

    Lye, R.C.M.; Toner, S.J.

    1987-01-01

    A novel diagnostic technique, which makes use of laser light scattered by soot particles, was used in an effort to identify the flame sheets within a natural gas diffusion flame. Soot particles, inherently created and consumed in the flame, were used as the scattering medium, which obviated the need for externally supplied seed material. Since no foreign material was added to the flame, the current technique can be considered truly nonintrusive. The soot distribution within a large buoyant natural gas diffusion flame is argued to be a reasonable marker of the flame sheets. Measurements made in 47.4-190 kW natural gas flames stabilized on a 0.5 m diameter burner show that the flame sheets are highly wrinkled and convoluted surfaces. The flame sheets are distributed fairly uniformly within the instantaneous volume of the flame, based on images of the associated soot, and the instantaneous flame volume is devoid of soot for 40-60% of the time. When soot is present, it is observed as thin sheets which become narrower in regions where the average strain rate is estimated to be greater.

  15. Diffuse large B-cell lymphoma mimicking advanced basal cell carcinoma.

    PubMed Central

    Akinyemi, Emmanuel; Mai, Le; Matin, Abu; Maini, Archana

    2007-01-01

    Primary cutaneous B-cell lymphomas (PCBCLs) are made up of a heterogenous group of B-cell lymphoproliferative diseases confined to the skin at the time of diagnosis with no evidence of extracutaneous involvement. With early diagnosis and adequate treatment, PCBCLs as a group has excellent prognosis, with about a 95% survival rate at five years. We report a case of diffuse large B-cell lymphoma (DLBCL) in a 52-year-old woman presenting as a fungating skin ulcer mimicking advanced basal cell carcinoma. Review of available literature showed most studies of PCBCLs being done on Europeans with no universally acceptable system of classification. Clinical findings, diagnostic evaluations and treatment outcomes of PCBCLs are discussed with emphasis on comparison of European Organization for Research and Treatment of Cancer (EORTC) and the World Health Organization (WHO) Classification of Neoplasms of the Hematopoietic and Lymphoid Tissue classification systems. Images Figure 1 Figure 2 PMID:17722675

  16. Diffuse large B-cell lymphoma mimicking advanced basal cell carcinoma.

    PubMed

    Akinyemi, Emmanuel; Mai, Le; Matin, Abu; Maini, Archana

    2007-08-01

    Primary cutaneous B-cell lymphomas (PCBCLs) are made up of a heterogenous group of B-cell lymphoproliferative diseases confined to the skin at the time of diagnosis with no evidence of extracutaneous involvement. With early diagnosis and adequate treatment, PCBCLs as a group has excellent prognosis, with about a 95% survival rate at five years. We report a case of diffuse large B-cell lymphoma (DLBCL) in a 52-year-old woman presenting as a fungating skin ulcer mimicking advanced basal cell carcinoma. Review of available literature showed most studies of PCBCLs being done on Europeans with no universally acceptable system of classification. Clinical findings, diagnostic evaluations and treatment outcomes of PCBCLs are discussed with emphasis on comparison of European Organization for Research and Treatment of Cancer (EORTC) and the World Health Organization (WHO) Classification of Neoplasms of the Hematopoietic and Lymphoid Tissue classification systems.

  17. Mechanism-Based Epigenetic Chemosensitization Therapy of Diffuse Large B Cell Lymphoma

    PubMed Central

    Clozel, Thomas; Yang, ShaoNing; Elstrom, Rebecca L.; Tam, Wayne; Martin, Peter; Kormaksson, Matthias; Banerjee, Samprit; Vasanthakumar, Aparna; Culjkovic, Biljana; Scott, David W.; Wyman, Sarah; Leser, Michael; Shaknovich, Rita; Chadburn, Amy; Tabbo, Fabrizio; Godley, Lucy A.; Gascoyne, Randy D.; Borden, Katherine L.; Inghirami, Giorgio; Leonard, John P.; Melnick, Ari; Cerchietti, Leandro

    2013-01-01

    Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemo-resistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTIs) reprogrammed chemo-resistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemo-resistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was performed evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk newly diagnosed DLBCL patients. The combination was well tolerated and yielded a high rate of complete remission. Pre and post azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs. PMID:23955273

  18. Discovery and Characterization of Super-Enhancer Associated Dependencies in Diffuse Large B-Cell Lymphoma

    PubMed Central

    Chapuy, Bjoern; McKeown, Michael R.; Lin, Charles Y.; Monti, Stefano; Roemer, Margaretha G.M.; Qi, Jun; Rahl, Peter B.; Sun, Heather H.; Yeda, Kelly T.; Doench, John G; Reichert, Elaine; Kung, Andrew L.; Rodig, Scott J.; Young, Richard A.; Shipp, Margaret A.; Bradner, James E.

    2014-01-01

    Summary Diffuse Large B-Cell Lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of BET bromodomain proteins in DLBCL, using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of BRD4 at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease. PMID:24332044

  19. Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma

    PubMed Central

    Yang, Yibin; Shaffer, Arthur L.; Emre, N.C. Tolga; Ceribelli, Michele; Zhang, Meili; Wright, George; Xiao, Wenming; Powell, John; Platig, John; Kohlhammer, Holger; Young, Ryan M.; Zhao, Hong; Yang, Yandan; Xu, Weihong; Buggy, Joseph J.; Balasubramanian, Sriram; Mathews, Lesley A.; Shinn, Paul; Guha, Rajarshi; Ferrer, Marc; Thomas, Craig; Waldmann, Thomas A.; Staudt, Louis M.

    2014-01-01

    Summary Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B-cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and also amplify pro-survival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor (BCR) signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies. PMID:22698399

  20. Jun-regulated genes promote interaction of diffuse large B-cell lymphoma with the microenvironment.

    PubMed

    Blonska, Marzenna; Zhu, Yifan; Chuang, Hubert H; You, M James; Kunkalla, Kranthi; Vega, Francisco; Lin, Xin

    2015-02-05

    Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with a high proliferation rate. However, the molecular and genetic features that drive the aggressive clinical behavior of DLBCL are not fully defined. Here, we have demonstrated that activated Jun signaling is a frequent event in DLBCL that promotes dissemination of malignant cells. Downregulation of Jun dramatically reduces lymphoma cell adhesion to extracellular matrix proteins, subcutaneous tumor size in nude mice, and invasive behavior, including bone marrow infiltration and interaction with bone marrow stromal cells. Furthermore, using a combination of RNA interference and gene expression profiling, we identified Jun target genes that are associated with disseminated lymphoma. Among them, ITGAV, FoxC1, and CX3CR1 are significantly enriched in patients with 2 or more extranodal sites. Our results point to activated Jun signaling as a major driver of the aggressive phenotype of DLBCL.

  1. Large Eddy Simulation Of Gravitational Effects In Transitional And Turbulent Gas-Jet Diffusion Flames

    NASA Technical Reports Server (NTRS)

    Jaberi, Farhad A.; Givi, Peyman

    2003-01-01

    The influence of gravity on the spatial and the compositional structures of transitional and turbulent hydrocarbon diffusion flames are studies via large eddy simulation (LES) and direct numerical simulation (DNS) of round and planar jets. The subgrid-scale (SGS) closures in LES are based on the filtered mass density function (FMDF) methodology. The FMDF represents the joint probability density function (PDF) of the SGS scalars, and is obtained by solving its transport equation. The fundamental advantage of LES/FMDF is that it accounts for the effects of chemical reaction and buoyancy exactly. The methodology is employed for capturing some of the fundamental influences of gravity in equilibrium flames via realistic chemical kinetic schemes. Some preliminary investigation of the gravity effects in non-equilibrium flames is also conducted, but with idealized chemical kinetics models.

  2. Diffuse Large B-Cell Lymphoma in the Era of Precision Oncology: How Imaging Is Helpful

    PubMed Central

    Shah, Hina J.; Jagannathan, Jyothi P.; Tirumani, Sree Harsha; Lele, Vikram R.; DiPiro, Pamela J.

    2017-01-01

    Diffuse large B cell lymphoma (DLBCL) is the most common histological subtype of Non-Hodgkin's lymphoma. As treatments continues to evolve, so do imaging strategies, and positron emission tomography (PET) has emerged as the most important imaging tool to guide oncologists in the diagnosis, staging, response assessment, relapse/recurrence detection,and therapeutic decision making of DLBCL. Other imaging modalities including magnetic resonance imaging (MRI), computed tomography (CT), ultrasound, and conventional radiography are also used in the evaluation of lymphoma. MRI is useful for nervous system and musculoskeletal system involvement and is emerging as a radiation free alternative to PET/CT. This article provides a comprehensive review of both the functional and morphological imaging modalities, available in the management of DLBCL. PMID:28096718

  3. A rare case of primary pulmonary diffuse large B cell lymphoma with CD5 positive expression

    PubMed Central

    Wang, Tao; Zhang, Mingming; Sun, Jianrong; Hao, Dong; Qi, Zhijiang; Lu, Feng; Ji, Hong; Liu, Weili; Wang, Xiaozhi

    2016-01-01

    Abstract Primary pulmonary diffuse large B-cell lymphoma (PPDLBCL) is extremely rare. Its clinical symptoms and signs are nonspe cific, and imaging features also have not yet been well-defined. Further description is important for the diagnosis and treatment of PPDLBCL. Herein, we reported a case of a patient who suffered from bilateral chest pain and dyspnea. Computed tomography (CT) of chest demonstrated bilateral lung mass, consolidations and reverse halo sign, while consolidations and reverse halo sign are uncommon according to previous reports. Tissue samples were taken by CT guided needle biopsy. The histological samples showed PPDLBCL. This case was special in view of positive expression of CD5. After the case was treated by cyclophosphamide pirarubicin vindesine dexamethasone (CHOP) chemotherapy for six courses, her clinical symptoms were partially alleviated, while CT showed progression disease. This case report highlights different imaging features and characteristics of molecular biology, and reviews study progress of PPDLBCL.

  4. Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma.

    PubMed

    Yang, Yibin; Kelly, Priscilla; Shaffer, Arthur L; Schmitz, Roland; Yoo, Hee Min; Liu, Xinyue; Huang, Da Wei; Webster, Daniel; Young, Ryan M; Nakagawa, Masao; Ceribelli, Michele; Wright, George W; Yang, Yandan; Zhao, Hong; Yu, Xin; Xu, Weihong; Chan, Wing C; Jaffe, Elaine S; Gascoyne, Randy D; Campo, Elias; Rosenwald, Andreas; Ott, German; Delabie, Jan; Rimsza, Lisa; Staudt, Louis M

    2016-04-11

    Chronic active B cell receptor (BCR) signaling, a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activate IκB kinase (IKK) and the classical NF-κB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-κB activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation. SMAC mimetics target cIAP1/2 for destruction, and consequently suppress NF-κB and selectively kill BCR-dependent ABC DLBCL lines, supporting their clinical evaluation in patients with ABC DLBCL.

  5. Gambogic acid induces apoptosis in diffuse large B-cell lymphoma cells via inducing proteasome inhibition.

    PubMed

    Shi, Xianping; Lan, Xiaoying; Chen, Xin; Zhao, Chong; Li, Xiaofen; Liu, Shouting; Huang, Hongbiao; Liu, Ningning; Zang, Dan; Liao, Yuning; Zhang, Peiquan; Wang, Xuejun; Liu, Jinbao

    2015-04-08

    Resistance to chemotherapy is a great challenge to improving the survival of patients with diffuse large B-cell lymphoma (DLBCL), especially those with activated B-cell-like DLBCL (ABC-DLBCL). Therefore it is urgent to search for novel agents for the treatment of DLBCL. Gambogic acid (GA), a small molecule derived from Chinese herb gamboges, has been approved for Phase II clinical trial for cancer therapy by Chinese FDA. In the present study, we investigated the effect of GA on cell survival and apoptosis in DLBCL cells including both GCB- and ABC-DLBCL cells. We found that GA induced growth inhibition and apoptosis of both GCB- and ABC-DLBCL cells in vitro and in vivo, which is associated with proteasome malfunction. These findings provide significant pre-clinical evidence for potential usage of GA in DLBCL therapy particularly in ABC-DLBCL treatment.

  6. CC-122 immunomodulatory effects in refractory patients with diffuse large B-cell lymphoma.

    PubMed

    Cubillos-Zapata, Carolina; Cordoba, Raúl; Avendaño-Ortiz, José; Arribas-Jiménez, Cristina; Hernández-Jiménez, Enrique; Toledano, Víctor; Villaescusa, Teresa; Moreno, Víctor; López-Collazo, Eduardo

    2016-01-01

    In the three patients included in a phase I clinical trial (NCT01421524), we report the immunomodulatory effects and efficacy of CC-122, a novel pleiotropic pathway modifier compound originally developed for broad diffuse large B-cell lymphoma (DLBCL). The chemical structure of CC-122 includes the glutarimide moiety that is known to modulate the immune response. The immunomodulatory agents including lenalidomide represent a promising therapeutic strategy targeting tumors in B-cell lymphoid malignancies. We observed that CC-122 might regulate the NK phenotype and its activity due to the reduced accumulation of myeloid-derived suppressor cell and eventually decrease the Tregs subsets. Finally, the activation of T cells through co-stimulatory molecule (CD28) was detected as a delayed CC-122 effect. In this context, CC-122 arises as an alternative option for DLBCL patients refractory to the traditional chemotherapeutic agents.

  7. Double hit diffuse large B-cell lymphomas: diagnostic and therapeutic challenges.

    PubMed

    Friedberg, Jonathan W

    2015-03-01

    Although diffuse large B-cell lymphoma (DLBCL) is curable with standard chemoimmunotherapy, over 30% of patients with advanced stage disease experience refractory disease or progression. Recent studies suggest that rearrangement of the myc oncogene occurs in approximately 10% of patients with DLBCL, and confers a very poor prognosis, particularly when there is concomitant rearrangement of bcl-2, a condition referred to as "double hit DLBCL". Using immunohistochemistry, up to 30% of patients have evidence of increased expression of myc, which occurs in both activated B-cell and germinal center type DLBCL. When bcl-2 is also positive by immunohistochemistry, prognosis is also poor. There are no randomized studies guiding treatment for patients with double hit DLBCL, but new datasets are emerging suggesting a possible role for dose-adjusted EPOCH infusional chemotherapy with rituximab. This review will conclude with a survey of novel agents which may be rationally incorporated into chemotherapy platforms for this high risk subset of DLBCL.

  8. Metabolic Signatures Uncover Distinct Targets in Molecular Subsets of Diffuse Large B-Cell Lymphoma

    PubMed Central

    Caro, Pilar; Kishan, Amar U.; Norberg, Erik; Stanley, Illana; Chapuy, Bjoern; Ficarro, Scott B.; Polak, Klaudia; Tondera, Daniel; Gounarides, John; Yin, Hong; Zhou, Feng; Green, Michael R.; Chen, Linfeng; Monti, Stefano; Marto, Jarrod A.; Shipp, Margaret A.; Danial, Nika N.

    2012-01-01

    SUMMARY Molecular signatures have identified several subsets of Diffuse Large B-Cell Lymphoma (DLBCL) and rational targets within the B-cell receptor (BCR) signaling axis. The OxPhos-DLBCL subset, which harbors the signature of genes involved in mitochondrial metabolism, is insensitive to inhibition of BCR survival signaling, but is functionally undefined. We show that compared with BCR-DLBCLs, OxPhos-DLBCLs display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons into the TCA cycle and increased glutathione levels. Importantly, perturbation of the fatty acid oxidation program and glutathione synthesis proved selectively toxic to this tumor subset. Our analysis provides evidence for distinct metabolic fingerprints and associated survival mechanisms in DLBCL and may have therapeutic implications. PMID:23079663

  9. Survival in patients with oral and maxillofacial diffuse large B-cell lymphoma.

    PubMed

    Guevara-Canales, Janet Ofelia; Morales-Vadillo, Rafael; Cava-Vergiú, Carlos Enrique; Leite, Fabiola Pessoa Pereira; Miranda Chaves Netto, Henrique Duque de; Soares, Fernando Augusto; Chaves, Maria das Graças Afonso Miranda

    2013-01-01

    The purpose of this study was to determine the survival and prognostic factors of patients with diffuse large B-cell lymphoma (DLBCL) of the oral cavity and maxillofacial region. Retrospectively, the clinical records of patients with a primary diagnosis of DLBCL of the oral cavity and maxillofacial region treated at the A.C. Camargo Hospital for Cancer, São Paulo, Brazil, between January 1980 and December 2005 were evaluated to determine (A) overall survival (OS) at 2 and 5 years and the individual survival percentage for each possible prognostic factor by means of the actuarial technique (also known as mortality tables), and the Kaplan Meier product limit method (which provided the survival value curves for each possible prognostic factor); (B) prognostic factors subject to univariate evaluation with the log-rank test (also known as Mantel-Cox), and multivariate analysis with Cox's regression model (all the variables together). The data were considered significant at p≤0.05. From 1980 to 2005, 3513 new cases of lymphomas were treated, of which 151 (4.3%) occurred in the oral cavity and maxillofacial region. Of these 151 lesions, 48 were diffuse large B-cell lymphoma, with 64% for OS at 2 years and 45% for OS at 5 years. Of the variables studied as possible prognostic factors, multivariate analysis found the following variables have statistically significant values: age (p=0.042), clinical stage (p=0.007) and performance status (p=0.031). These data suggest that patients have a higher risk of mortality if they are older, at a later clinical stage, and have a higher performance status.

  10. Large photocurrents in single layer graphene thin films: effects of diffusion and drift

    NASA Astrophysics Data System (ADS)

    Loomis, James; Panchapakesan, Balaji

    2012-07-01

    This paper reports large photocurrents in air-assisted depositions of single layer graphene (derived from reduced single layer graphene oxide) upon illumination with near-infrared (NIR) light. NIR-induced charge carrier generation and subsequent separation at the metal-graphene interface resulted in photocurrent generation. Varying bias voltages were applied to test samples and allowed for evaluating photoresponses in either diffusion- or drift-dominated regions. In the diffusion-dominated region, position-dependent effects of photoconductivity were demonstrated. The photocurrent exhibited increase when the positive electrode was illuminated, decrease when the negative electrode was illuminated, and negligible response when the area between the electrodes was illuminated. At a 100 μV bias voltage, a per cent change in current from ˜150% (40 mW NIR) to ˜1800% (335 mW NIR) is reported. Such large photocurrent responses result from built-in electric fields and optically generated temperature gradients (maximum NIR-induced temperature rise ˜70 °C). The per cent photocurrent change was observed to depend on both annealing temperature and NIR power, but not resistance value. In the drift-dominated realm, a Gaussian photocurrent profile was obtained, signaling drift of charge carriers with increase in localized electric field, akin to the classic Haynes-Shockley experiment. A minority carrier mobility value of μ ˜ 700 cm2 V -1 s-1 is reported. The simple low cost graphene devices presented in this paper were fabricated without lithographic processing and are ideal candidates for assorted infrared imaging applications.

  11. Large photocurrents in single layer graphene thin films: effects of diffusion and drift.

    PubMed

    Loomis, James; Panchapakesan, Balaji

    2012-07-05

    This paper reports large photocurrents in air-assisted depositions of single layer graphene (derived from reduced single layer graphene oxide) upon illumination with near-infrared (NIR) light. NIR-induced charge carrier generation and subsequent separation at the metal-graphene interface resulted in photocurrent generation. Varying bias voltages were applied to test samples and allowed for evaluating photoresponses in either diffusion- or drift-dominated regions. In the diffusion-dominated region, position-dependent effects of photoconductivity were demonstrated. The photocurrent exhibited increase when the positive electrode was illuminated, decrease when the negative electrode was illuminated, and negligible response when the area between the electrodes was illuminated. At a 100 μV bias voltage, a per cent change in current from ∼150% (40 mW NIR) to ∼1800% (335 mW NIR) is reported. Such large photocurrent responses result from built-in electric fields and optically generated temperature gradients (maximum NIR-induced temperature rise ∼70 °C). The per cent photocurrent change was observed to depend on both annealing temperature and NIR power, but not resistance value. In the drift-dominated realm, a Gaussian photocurrent profile was obtained, signaling drift of charge carriers with increase in localized electric field, akin to the classic Haynes-Shockley experiment. A minority carrier mobility value of μ ∼700 cm² V⁻¹ s⁻¹ is reported. The simple low cost graphene devices presented in this paper were fabricated without lithographic processing and are ideal candidates for assorted infrared imaging applications.

  12. Quantitative image analysis in the assessment of diffuse large B-cell lymphoma.

    PubMed

    Chabot-Richards, Devon S; Martin, David R; Myers, Orrin B; Czuchlewski, David R; Hunt, Kristin E

    2011-12-01

    Proliferation rates in diffuse large B-cell lymphoma have been associated with conflicting outcomes in the literature, more often with high proliferation associated with poor prognosis. In most studies, the proliferation rate was estimated by a pathologist using an immunohistochemical stain for the monoclonal antibody Ki-67. We hypothesized that a quantitative image analysis algorithm would give a more accurate estimate of the proliferation rate, leading to better associations with survival. In all, 84 cases of diffuse large B-cell lymphoma were selected according to the World Health Organization criteria. Ki-67 percentage positivity estimated by the pathologist was recorded from the original report. The same slides were then scanned using an Aperio ImageScope, and Ki-67 percentage positivity was calculated using a computer-based quantitative immunohistochemistry nuclear algorithm. In addition, chart review was performed and survival time was recorded. The Ki-67 percentage estimated by the pathologist from the original report versus quantitative image analysis was significantly correlated (P<0.001), but pathologist Ki-67 percentages were significantly higher than quantitative image analysis (P=0.021). There was less agreement at lower Ki-67 percentages. Comparison of Ki-67 percentage positivity versus survival did not show significant association either with pathologist estimate or quantitative image analysis. However, although not significant, there was a trend of worse survival at higher proliferation rates detected by the pathologist but not by quantitative image analysis. Interestingly, our data suggest that the Ki-67 percentage positivity as assessed by the pathologist may be more closely associated with survival outcome than that identified by quantitative image analysis. This may indicate that pathologists are better at selecting appropriate areas of the slide. More cases are needed to assess whether this finding would be statistically significant. Due to

  13. Detection and outcome of occult leptomeningeal disease in diffuse large B-cell lymphoma and Burkitt lymphoma.

    PubMed

    Wilson, Wyndham H; Bromberg, Jacoline E C; Stetler-Stevenson, Maryalice; Steinberg, Seth M; Martin-Martin, Lourdes; Muñiz, Carmen; Sancho, Juan Manuel; Caballero, Maria Dolores; Davidis, Marjan A; Brooimans, Rik A; Sanchez-Gonzalez, Blanca; Salar, Antonio; González-Barca, Eva; Ribera, Jose Maria; Shovlin, Margaret; Filie, Armando; Dunleavy, Kieron; Mehrling, Thomas; Spina, Michele; Orfao, Alberto

    2014-07-01

    The benefit of intrathecal therapy and systemic rituximab on the outcome of diffuse large B-cell lymphoma at risk of central nervous system disease is controversial. Furthermore, the effect of intrathecal treatment and rituximab in diffuse large B-cell and Burkitt lymphoma with occult leptomeningeal disease detected by flow cytometry at diagnosis is unknown. Untreated diffuse large B-cell (n=246) and Burkitt (n=80) lymphoma at clinical risk of central nervous system disease and having had pre-treatment cerebrospinal fluid were analyzed by flow cytometry and cytology. Spinal fluid involvement was detected by flow cytometry alone (occult) in 33 (13%) diffuse large B-cell and 9 (11%) Burkitt lymphoma patients, and detected by cytology in 11 (4.5%) and 5 (6%) patients, respectively. Diffuse large B-cell lymphoma with occult spinal fluid involvement had poorer survival (P=0.0001) and freedom from central nervous system relapse (P<0.0001) compared to negative cases. Burkitt lymphoma with occult spinal fluid involvement had an inferior freedom from central nervous system relapse (P=0.026) but not survival. The amount of intrathecal chemotherapy was quantitatively associated with survival in diffuse large B-cell lymphoma with (P=0.02) and without (P=0.001) occult spinal fluid involvement. However, progression of systemic disease and not control of central nervous system disease was the principal cause of treatment failure. In diffuse large B-cell lymphoma, systemic rituximab was associated with improved freedom from central nervous system relapse (P=0.003) but not with survival. Our results suggest that patients at risk of central nervous system disease should be evaluated by flow cytometry and that intrathecal prophylaxis/therapy is beneficial.

  14. Traditional beliefs about the cause of AIDS and AIDS-related stigma in South Africa.

    PubMed

    Kalichman, S C; Simbayi, L

    2004-07-01

    AIDS-related stigmas are pervasive in some segments of South African society and stigmas can impede efforts to promote voluntary counselling and testing and other HIV-AIDS prevention efforts. The current study examined associations among the belief that AIDS is caused by spirits and supernatural forces, AIDS-related knowledge and AIDS-related stigmas. A street intercept survey with 487 men and women living in a Black township in Cape Town, South Africa showed that 11% (n=54) believed that AIDS is caused by spirits and supernatural forces, 21% (n=105) were unsure if AIDS is caused by spirits and the supernatural, and 68% (n=355) did not believe that AIDS is caused by spirits and supernatural forces. Multiple logistic regression analyses controlling for participant age, gender, years of education and survey venue showed that people who believed HIV-AIDS is caused by spirits and the supernatural demonstrated significantly more misinformation about AIDS and were significantly more likely to endorse repulsion and social sanction stigmatizing beliefs against people living with HIV-AIDS. However, nearly all associations between beliefs that AIDS is caused by spirits and AIDS stigmas were non-significant when logistic regressions were repeated with AIDS-related knowledge included as a control variable. This finding suggests that relationships between traditional beliefs about the cause of HIV-AIDS and AIDS stigmas are mediated by AIDS-related knowledge. AIDS education efforts are urgently needed to reach people who hold traditional beliefs about AIDS to remedy AIDS stigmas.

  15. Spectroscopic Confirmation of the Existence of Large, Diffuse Galaxies in the Coma Cluster

    NASA Astrophysics Data System (ADS)

    van Dokkum, Pieter G.; Romanowsky, Aaron J.; Abraham, Roberto; Brodie, Jean P.; Conroy, Charlie; Geha, Marla; Merritt, Allison; Villaume, Alexa; Zhang, Jielai

    2015-05-01

    We recently identified a population of low surface brightness objects in the field of the z = 0.023 Coma cluster, using the Dragonfly Telephoto Array. Here we present Keck spectroscopy of one of the largest of these “ultra-diffuse galaxies” (UDGs), confirming that it is a member of the cluster. The galaxy has prominent absorption features, including the Ca ii H+K lines and the G-band, and no detected emission lines. Its radial velocity of cz = 6280 ± 120 km s-1 is within the 1σ velocity dispersion of the Coma cluster. The galaxy has an effective radius of 4.3 ± 0.3 kpc and a Sérsic index of 0.89 ± 0.06, as measured from Keck imaging. We find no indications of tidal tails or other distortions, at least out to a radius of ˜ 2{{r}e}. We show that UDGs are located in a previously sparsely populated region of the size—magnitude plane of quiescent stellar systems, as they are ˜6 mag fainter than normal early-type galaxies of the same size. It appears that the luminosity distribution of large quiescent galaxies is not continuous, although this could largely be due to selection effects. Dynamical measurements are needed to determine whether the dark matter halos of UDGs are similar to those of galaxies with the same luminosity or to those of galaxies with the same size.

  16. Rituximab in the treatment of diffuse large B-cell lymphoma primary of the lung.

    PubMed

    Aviles, Agustin; Nambo, Maria J; Huerta-Guzman, Judith; Silva, Luis; Neri, Natividad

    2013-03-01

    Diffuse large B-cell lymphoma primary of lung (DLBCL-PL) is a rare presentation of extranodal lymphoma, in most cases chemotherapy-based anthracyclines: CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the treatment, with excellent outcome. The addition of rituximab to CHOP (R-CHOP) has been considered the gold standard in the treatment of nodal DLBCL. Thus, we assess in a large number of cases of DLBCL-PL whether the use of R-CHOP could improve survival in this setting of patients. Forty-two patients with DLBCL-PL, stage IE, age 65 years or younger, were treated with standard R-CHOP, no consolidation radiotherapy or maintenance therapy were considered. They were matched with patients who received CHOP alone to assess efficacy and toxicity. Complete response was observed in 35 patients (83%), and 7 patients were considered failure (16%). The study has a median follow-up of 42.8 months. Actuarial curves at 5 years showed that progression-free survival was 88 % and overall survival was 70 %. The results were not statistically different when compared retrospectively with patients who received CHOP alone. Treatment was well tolerated. The addition of rituximab to chemotherapy did not improve outcome in patients with DLBCL-PL.

  17. Clinical implications of the molecular subtypes of diffuse large B-cell lymphoma.

    PubMed

    Hill, Brian T; Sweetenham, John

    2012-05-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma and responds to standard treatment with chemoimmunotherapy in most patients. Standard prognostic scoring systems such as the International Prognostic Index (IPI) are useful for risk stratification, but are unreliable in predicting outcomes in individual patients because of the biologic heterogeneity of this disease. Gene expression profiling has revealed molecular subtypes of DLBCL: those derived from the lymph node germinal center (GCB) and others derived from an activated B-cell (ABC). A third entity, primary mediastinal B-cell lymphoma (unclassifiable DLBCL), displays pathobiologic features distinct from ABC and GCB subtypes. Patients with ABC-DLBCL have inferior progression-free survival and overall survival relative to those with the GCB subtype. In conclusion, molecular subtyping is a powerful tool for discriminating cases of DLBCL into groups that display very disparate biology and clinical outcomes. Although immunohistochemistry (IHC)-based algorithms predict both the molecular subtype as defined by gene expression profiling and clinical outcomes with reasonable concordance, not all experienced centers have been able to reproduce these findings. As techniques to subclassify DLBCL become universally adopted, large prospective trials will be needed to confirm the benefit of therapy tailored to molecular subtype.

  18. EBV-positive diffuse large B-cell lymphoma of the elderly.

    PubMed

    Ok, Chi Young; Papathomas, Thomas G; Medeiros, L Jeffrey; Young, Ken H

    2013-07-18

    Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly, initially described in 2003, is a provisional entity in the 2008 World Health Organization classification system and is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in patients >50 years of age and in whom there is no known immunodeficiency or history of lymphoma. These tumors are more common in Asia but also occur in North America and Europe at a low frequency. These neoplasms exhibit a morphologic continuum, from polymorphous to monomorphous, but morphologic features do not correlate with prognosis as all patients have a clinically aggressive course. Most EBV-positive DLBCL of the elderly patients have an activated B-cell immunophenotype and are characterized by prominent nuclear factor-κB activation. Cytogenetic complexity is usually low. In this review, we comprehensively delineate the data emerging from analyses of EBV latency program, microRNA-mediated EBV viral oncogenesis, functional genomics of EBV and its biology, and differential diagnosis challenge for EBV-positive DLBCL of the elderly. It is hoped that the improved understanding of these tumors will lead to the development of novel therapeutic approaches, enhance the effectiveness of clinical trials, and improve prognosis.

  19. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma.

    PubMed

    Davis, R Eric; Ngo, Vu N; Lenz, Georg; Tolar, Pavel; Young, Ryan M; Romesser, Paul B; Kohlhammer, Holger; Lamy, Laurence; Zhao, Hong; Yang, Yandan; Xu, Weihong; Shaffer, Arthur L; Wright, George; Xiao, Wenming; Powell, John; Jiang, Jian-Kang; Thomas, Craig J; Rosenwald, Andreas; Ott, German; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D; Connors, Joseph M; Johnson, Nathalie A; Rimsza, Lisa M; Campo, Elias; Jaffe, Elaine S; Wilson, Wyndham H; Delabie, Jan; Smeland, Erlend B; Fisher, Richard I; Braziel, Rita M; Tubbs, Raymond R; Cook, J R; Weisenburger, Dennis D; Chan, Wing C; Pierce, Susan K; Staudt, Louis M

    2010-01-07

    A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models, but genetic and functional evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). The signalling adaptor CARD11 is required for constitutive NF-kappaB pathway activity and survival in ABC DLBCL. Roughly 10% of ABC DLBCLs have mutant CARD11 isoforms that activate NF-kappaB, but the mechanism that engages wild-type CARD11 in other ABC DLBCLs was unknown. An RNA interference genetic screen revealed that a BCR signalling component, Bruton's tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11. In addition, knockdown of proximal BCR subunits (IgM, Ig-kappa, CD79A and CD79B) killed ABC DLBCLs with wild-type CARD11 but not other lymphomas. The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt's lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase, a feedback inhibitor of BCR signalling. These findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.

  20. Experimental Mating of Trapped Vortex Diffusers with Large Area Ratio Thrust Augmentors

    DTIC Science & Technology

    1974-09-01

    the hump and greatly reduce the desired effect of the cavity. Consequently, the diffuser would not operate properly. It was also found that, due to...differences. Differences In laboratory constraints (wails, ceiling, etc.) can also have a small effect on the ejector flow. 2. TRAPPED VORTEX DIFFUSER...was farther from complete at the smaller lengths. The shift in peak locations seems to be a simple diffuser effect where the flow with the thinnest

  1. Tracheal ulcer due to Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly.

    PubMed

    Ito, Takeo; Fujisaki, Hideaki; Nishio, Suehiro; Hiroshige, Shigeo; Miyazaki, Eishi; Kadota, Jun-ichi

    2014-03-01

    A 74-year-old man was referred to our hospital because of a tracheal stenosis circumscribed with soft tissue density and a left pulmonary nodule. Open biopsy of a right submandibular lymph node revealed diffuse large B-cell lymphoma, and the malignant cells were positive for Epstein-Barr virus gene products. Bronchofiberscopy revealed a tracheal necrotizing ulcer. After chemotherapy, the tracheal ulcer resolved. To our knowledge, this is the first report of a case of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly with a tracheal ulcer.

  2. A large-area diffuse air discharge plasma excited by nanosecond pulse under a double hexagon needle-array electrode.

    PubMed

    Liu, Zhi-Jie; Wang, Wen-Chun; Yang, De-Zheng; Wang, Sen; Zhang, Shuai; Tang, Kai; Jiang, Peng-Chao

    2014-01-01

    A large-area diffuse air discharge plasma excited by bipolar nanosecond pulse is generated under a double hexagon needle-array electrode at atmospheric pressure. The images of the diffuse discharge, electric characteristics, and the optical emission spectra emitted from the diffuse air discharge plasma are obtained. Based on the waveforms of pulse voltage and current, the power consumption, and the power density of the diffuse air discharge plasma are investigated under different pulse peak voltages. The electron density and the electron temperature of the diffuse plasma are estimated to be approximately 1.42×10(11) cm(-3) and 4.4 eV, respectively. The optical emission spectra are arranged to determine the rotational and vibrational temperatures by comparing experimental with simulated spectra. Meanwhile, the rotational and vibrational temperatures of the diffuse discharge plasma are also discussed under different pulse peak voltages and pulse repetition rates, respectively. In addition, the diffuse air discharge plasma can form an area of about 70×50 mm(2) on the surface of dielectric layer and can be scaled up to the required size.

  3. Child Abuse and Aids-Related Knowledge, Attitudes and Behavior among Adolescents in Zambia

    ERIC Educational Resources Information Center

    Slonim-Nevo, Vered; Mukuka, Lawrence

    2007-01-01

    Objective: To research the correlation between physical and sexual abuse by family members and AIDS-related knowledge, attitudes, self-efficacy and behavior among urban and rural adolescents in Zambia. Sample: The sample comprises 3,360 adolescents, aged 10-19, from urban and rural Zambia; 2,160 of them attended school, while 1,200 of them did…

  4. Exploring AIDS-Related Knowledge, Attitudes, and Behaviors of Female Mexican Migrant Workers.

    ERIC Educational Resources Information Center

    Organista, Pamela Balls; Organista, Kurt C.; Soloff, Pearl R.

    1998-01-01

    AIDS-related knowledge, attitudes, and behaviors were assessed among female migrant laborers (N=32). Results are reported regarding knowledge and beliefs about AIDS transmission, knowledge and beliefs about condom use, and actual use of condoms. Needs for health education and services, sexual power, and other implications of findings are…

  5. [Central nervous system relapse in diffuse large B cell lymphoma: Risk factors].

    PubMed

    Sancho, Juan-Manuel; Ribera, Josep-Maria

    2016-01-15

    Central nervous system (CNS) involvement by lymphoma is a complication associated, almost invariably, with a poor prognosis. The knowledge of the risk factors for CNS relapse is important to determine which patients could benefit from prophylaxis. Thus, patients with very aggressive lymphomas (such as lymphoblastic lymphoma or Burkitt's lymphoma) must systematically receive CNS prophylaxis due to a high CNS relapse rate (25-30%), while in patients with indolent lymphoma (such as follicular lymphoma or marginal lymphoma) prophylaxis is unnecessary. However, the question about CNS prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, remains controversial. The information available is extensive, mainly based on retrospective and heterogeneous studies. There seems that immunochemotherapy based on rituximab reduces the CNS relapse rate. On the other hand, patients with increased serum lactate dehydrogenase plus more than one extranodal involvement seem to have a higher risk of CNS relapse, but a prophylaxis strategy based only on the presence of these 2 factors does not prevent all CNS relapses. Patients with involvement of testes or breast have high risk of CNS relapse and prophylaxis is mandatory. Finally, CNS prophylaxis could be considered in patients with DLBCL and renal or epidural space involvement, as well as in those cases with MYC rearrangements, although additional studies are necessary.

  6. Development tuberculous meningitis during chemotherapy for CD5-positive diffuse large B-cell lymphoma.

    PubMed

    Teramura, Yuki; Kameda, Kazuaki; Kanda, Junya; Gomyo, Ayumi; Hayakawa, Jin; Akahoshi, Yu; Komiya, Yusuke; Harada, Naonori; Ugai, Tomotaka; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Sato, Miki; Wada, Hidenori; Terasako-Saito, Kiriko; Kimura, Shun-Ichi; Kikuchi, Misato; Nakasone, Hideki; Kako, Shinichi; Kanda, Yoshinobu

    2016-05-01

    The patient was a 62-year-old woman with CD5(+) diffuse large B-cell lymphoma. Treatment with the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) was started. On the eleventh day of the third cycle, headache and low grade fever developed. Her consciousness gradually deteriorated. Seven days after symptom onset, she was brought to the emergency department of our hospital. Cerebrospinal fluid (CSF) analysis revealed a white blood cell count of 25/μl, and a protein level of 188 mg/dl. Antibacterial and antiviral agents were administered based on a diagnosis of acute meningitis. She showed no improvement. We performed another lumbar puncture and intrathecal chemotherapy, a combination of methotrexate and dexamethasone, was administered because we suspected central nervous system involvement of lymphoma. She showed transient improvement. On day 12, we started the R-MPV regimen (rituximab, methotrexate, procarbazine, and vincristine). However, fever and disturbance of consciousness persisted. On day 20, we empirically started anti-tuberculosis treatment. Four days later, tubercle bacilli were confirmed by CSF culture after a 23-day incubation. We ultimately confirmed a diagnosis of tuberculous meningitis. Impaired cellular immunity in lymphoma patients increases the risk of tuberculosis. It is important to consider tuberculous meningitis in the differential diagnosis of a lymphoma patient presenting with meningitis.

  7. Anisotropic heat diffusion on stochastic magnetic field in the Large Helical Device

    NASA Astrophysics Data System (ADS)

    Suzuki, Yasuhiro

    2016-10-01

    The magnetic topology is a key issue in fusion plasma researches. An example is the Resonant Magnetic Perturbation (RMP) to control the transport and MHD activities in tokamak and stellarator experiments. However, the physics how the RMP affects the transport and MHD is not clear. One reason is a role of the magnetic topology is unclear. That problem is connecting to the identification of the magnetic topology in the experiment. In the experiment, the finite temperature gradient is observed on the stochastic field where is stochastized by the theoretical prediction. In a classical theory, the electron temperature gradient should be zero on the stochastic magnetic field. We need to study the stochastic magnetic field can keep the finite temperature gradient or not. In this study, we study the anisotropic heat diffusion equation to simulate the heat transport on the stochastic magnetic field. Changing a ratio of κ∥ and κ⊥, the distribution of the temperature on the stochastic magnetic field is obtained. Hudson et al. pointed out the KAM surface is a barrier to keep the finite temperature. We simulate those results in realistic magnetic field of the Large Helical Device.

  8. DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma

    PubMed Central

    Shaknovich, Rita; Geng, Huimin; Johnson, Nathalie A.; Tsikitas, Lucas; Cerchietti, Leandro; Greally, John M.

    2010-01-01

    Expression profiling has shown 2 main and clinically distinct subtypes of diffuse large B-cell lymphomas (DLBCLs): germinal-center B cell–like (GCB) and activated B cell–like (ABC) DLBCLs. Further work has shown that these subtypes are partially characterized by distinct genetic alterations and different survival. Here, we show with the use of an assay that measures DNA methylation levels of 50 000 CpG motifs distributed among more than 14 000 promoters that these 2 DLBCL subtypes are also characterized by distinct epigenetic profiles. DNA methylation and gene expression profiling were performed on a cohort of 69 patients with DLBCL. After assigning ABC or GCB labels with a Bayesian expression classifier trained on an independent dataset, a supervised analysis identified 311 differentially methylated probe sets (263 unique genes) between ABC and GCB DLBCLs. Integrated analysis of methylation and gene expression showed a core tumor necrosis factor-α signaling pathway as the principal differentially perturbed gene network. Sixteen genes overlapped between the core ABC/GCB methylation and expression signatures and encoded important proteins such as IKZF1. This reduced gene set was an accurate predictor of ABC and GCB subtypes. Collectively, the data suggest that epigenetic patterning contributes to the ABC and GCB DLBCL phenotypes and could serve as useful biomarker. PMID:20610814

  9. Acute myelofibrosis in a patient with diffuse large cell non Hodgkin's lymphoma and renal cancer.

    PubMed

    Mohren, Martin; Essbach, Uwe; Franke, Astrid; Klink, Anne; Maas, Christian; Markmann, Ilka; Pelz, Antje F; Jentsch-Ullrich, Kathleen

    2003-09-01

    Relapse after anthracycline based combination chemotherapy is frequently seen in patients with aggressive non Hodgkin's Lymphomas (NHL), whereas complications such as secondary leukemia or solid tumor rarely occur. We report a patient with diffuse large cell (DLC) NHL and concurrent renal cancer, who developed acute myelofibrosis (AMF) later in the course of her disease. This 60-year-old female patient presented with pancytopenia and a right sided renal mass. Diagnostic work up revealed severe bone marrow infiltration by DLC NHL and renal cancer T1N0M0G2. Cytogenetic and molecular evaluation of bone marow cells showed three distinct clones, (a normal 46XX karyotype, a ringed chromosome 7 and a third clone with an enlarged chromosome 2 as well as several fragments). The patient underwent nephrectomy and eventually received 6 cycles of CHOP 14 chemotherapy. Anemia persisted followed by severe granulocytopenia and thrombocytopenia 6 weeks later. Repeated bone marrow biopsy showed absence of lymphoma and/or cancer metastasis, but massive myelofibrosis with an increased number of atypical megakaryocytes. Considering the short clinical course and the absence of hepatosplenomegaly AMF was diagnosed. The concurrence of three distinctneoplasms within a short period of time as well as the complex cytogenetic aberrations found in her bone marrow cells reflect a strong individual susceptibility to malignant disease in this patient.

  10. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma.

    PubMed

    Cerhan, James R; Berndt, Sonja I; Vijai, Joseph; Ghesquières, Hervé; McKay, James; Wang, Sophia S; Wang, Zhaoming; Yeager, Meredith; Conde, Lucia; de Bakker, Paul I W; Nieters, Alexandra; Cox, David; Burdett, Laurie; Monnereau, Alain; Flowers, Christopher R; De Roos, Anneclaire J; Brooks-Wilson, Angela R; Lan, Qing; Severi, Gianluca; Melbye, Mads; Gu, Jian; Jackson, Rebecca D; Kane, Eleanor; Teras, Lauren R; Purdue, Mark P; Vajdic, Claire M; Spinelli, John J; Giles, Graham G; Albanes, Demetrius; Kelly, Rachel S; Zucca, Mariagrazia; Bertrand, Kimberly A; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Hutchinson, Amy; Zhi, Degui; Habermann, Thomas M; Link, Brian K; Novak, Anne J; Dogan, Ahmet; Asmann, Yan W; Liebow, Mark; Thompson, Carrie A; Ansell, Stephen M; Witzig, Thomas E; Weiner, George J; Veron, Amelie S; Zelenika, Diana; Tilly, Hervé; Haioun, Corinne; Molina, Thierry Jo; Hjalgrim, Henrik; Glimelius, Bengt; Adami, Hans-Olov; Bracci, Paige M; Riby, Jacques; Smith, Martyn T; Holly, Elizabeth A; Cozen, Wendy; Hartge, Patricia; Morton, Lindsay M; Severson, Richard K; Tinker, Lesley F; North, Kari E; Becker, Nikolaus; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; Staines, Anthony; Lightfoot, Tracy; Crouch, Simon; Smith, Alex; Roman, Eve; Diver, W Ryan; Offit, Kenneth; Zelenetz, Andrew; Klein, Robert J; Villano, Danylo J; Zheng, Tongzhang; Zhang, Yawei; Holford, Theodore R; Kricker, Anne; Turner, Jenny; Southey, Melissa C; Clavel, Jacqueline; Virtamo, Jarmo; Weinstein, Stephanie; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Trichopoulos, Dimitrios; Vermeulen, Roel C H; Boeing, Heiner; Tjonneland, Anne; Angelucci, Emanuele; Di Lollo, Simonetta; Rais, Marco; Birmann, Brenda M; Laden, Francine; Giovannucci, Edward; Kraft, Peter; Huang, Jinyan; Ma, Baoshan; Ye, Yuanqing; Chiu, Brian C H; Sampson, Joshua; Liang, Liming; Park, Ju-Hyun; Chung, Charles C; Weisenburger, Dennis D; Chatterjee, Nilanjan; Fraumeni, Joseph F; Slager, Susan L; Wu, Xifeng; de Sanjose, Silvia; Smedby, Karin E; Salles, Gilles; Skibola, Christine F; Rothman, Nathaniel; Chanock, Stephen J

    2014-11-01

    Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.

  11. Are we ready to stratify treatment for diffuse large B-cell lymphoma using molecular hallmarks?

    PubMed

    Barton, Sarah; Hawkes, Eliza A; Wotherspoon, Andrew; Cunningham, David

    2012-01-01

    The division of the heterogeneous entity of diffuse large B-cell lymphoma (DLBCL) into the ontogenic phenotypes of germinal center B-cell-like (GCB) and activated B-cell-like (ABC) is optimally determined by gene expression profiling (GEP), although simpler immunohistochemistry (IHC) algorithms are alternatively being used. The cell-of-origin (COO) classification assists in prognostication and may be predictive of response to therapy. Mounting data suggests that IHC methods of classifying COO may be inaccurate. GEP categorization of COO is superior in defining prognostically and biologically distinct DLBCL subtypes, but current barriers to its widescale use include inaccessibility, cost, and lack of methodological standardization and prospective validation. The poorer prognosis of ABC-DLBCL is frequently associated with constitutive activity in the NF-κB pathway and aberrations in upstream or downstream regulators of this pathway. The molecular mechanisms underlying lymphomagenesis in GCB-DLBCL are arguably less well defined, but C-REL amplification and mutations in BCL-2 and EZH2 are common. New technologies, such as next-generation sequencing, are rapidly revealing novel pathogenic genetic aberrations, and DLBCL treatment strategies are increasingly being designed focusing on distinctive pathogenic drivers within ontogenic phenotypes. This review examines emerging molecular targets and novel therapeutic agents in DLBCL, and discusses whether stratifying therapy for DLBCL using molecular features is merited by current preclinical and clinical evidence.

  12. Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma

    PubMed Central

    Cardenas, Mariano G.; Yu, Wenbo; Beguelin, Wendy; Teater, Matthew R.; Geng, Huimin; Goldstein, Rebecca L.; Oswald, Erin; Hatzi, Katerina; Yang, Shao-Ning; Cohen, Joanna; Shaknovich, Rita; Vanommeslaeghe, Kenno; Cheng, Huimin; Liang, Dongdong; Cho, Hyo Je; Tam, Wayne; Du, Wei; Leonard, John P.; Elemento, Olivier; Cierpicki, Tomasz; Xue, Fengtian; MacKerell, Alexander D.; Melnick, Ari M.

    2016-01-01

    Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands. PMID:27482887

  13. Diffuse large B-cell lymphoma presenting in the leukemic phase.

    PubMed

    Pires, Patricia Puccetti; Kanegae, Marcia Yoshie; Rays, Jairo; Catania, Marcos; Lima, Fabiana Roberto; Noronha, Thiago Rodrigo; Abdo, Andre Neder Ramires; Pereira, Juliana

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma comprising a heterogeneous group of disorders with variable histological and clinical behavior. Although other lymphomas may present in the leukemic phase more frequently, this appearance is unusually observed among DLBCL cases. Diagnosing lymphoma is not always easy, and the patient's clinical status quite often may hamper invasive procedures for diagnosis pushing the clinician to look for alternatives to reach the nearest possible accurate diagnosis. The authors report the case of a middle-aged man who presented the history of malaise, weight loss, and low-grade fever. The peripheral blood count showed leukocytosis with the presence of blasts and thrombocytopenia. The cytological morphology and immunophenotyping of the peripheral blood and bone marrow aspirate, as well as the bone marrow biopsy accompanied by a thorough immunohistochemical analysis, rendered the diagnosis of DLBCL in the leukemic phase. The patient was prescribed R-CHOP with a favorable outcome. Intra-abdominal lymph node biopsy was avoided because of the patient's critical medical condition. The authors highlight this rare form of presentation of DLBCL as well as the combination of peripheral blood, bone marrow aspirate, and bone marrow biopsy for reaching the diagnosis in cases were a lymph node sample is unavailable for the diagnostic work-up.

  14. Diffuse large B-cell lymphoma presenting in the leukemic phase

    PubMed Central

    Pires, Patricia Puccetti; Rays, Jairo; Catania, Marcos; Lima, Fabiana Roberto; Noronha, Thiago Rodrigo; Abdo, Andre Neder Ramires; Pereira, Juliana

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma comprising a heterogeneous group of disorders with variable histological and clinical behavior. Although other lymphomas may present in the leukemic phase more frequently, this appearance is unusually observed among DLBCL cases. Diagnosing lymphoma is not always easy, and the patient's clinical status quite often may hamper invasive procedures for diagnosis pushing the clinician to look for alternatives to reach the nearest possible accurate diagnosis. The authors report the case of a middle-aged man who presented the history of malaise, weight loss, and low-grade fever. The peripheral blood count showed leukocytosis with the presence of blasts and thrombocytopenia. The cytological morphology and immunophenotyping of the peripheral blood and bone marrow aspirate, as well as the bone marrow biopsy accompanied by a thorough immunohistochemical analysis, rendered the diagnosis of DLBCL in the leukemic phase. The patient was prescribed R-CHOP with a favorable outcome. Intra-abdominal lymph node biopsy was avoided because of the patient's critical medical condition. The authors highlight this rare form of presentation of DLBCL as well as the combination of peripheral blood, bone marrow aspirate, and bone marrow biopsy for reaching the diagnosis in cases were a lymph node sample is unavailable for the diagnostic work-up. PMID:27284540

  15. Low T3 syndrome is a strong prognostic predictor in diffuse large B cell lymphoma.

    PubMed

    Gao, Rui; Liang, Jin-Hua; Wang, Li; Zhu, Hua-Yuan; Wu, Wei; Wu, Jia-Zhu; Xia, Yi; Cao, Lei; Fan, Lei; Yang, Tao; Li, Jian-Yong; Xu, Wei

    2017-02-01

    The aim of this study was to evaluate the prognostic effect of low triiodothyronine (T3) syndrome on patients with diffuse large B cell lymphoma (DLBCL). A hundred and eighty-eight patients with detailed thyroid hormone levels at diagnosis of DLBCL were enrolled. Low T3 syndrome was defined as a low serum free T3 (FT3) level with low or normal serum free tetraiodothyronine (FT4) and thyroid stimulating hormone levels. Multivariate Cox regression analysis was used to screen prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Receiver-operator characteristic curves and the corresponding areas under the curve were calculated to assess the predictive accuracy of International Prognostic Index (IPI) and low T3 syndrome. Twenty-four patients were diagnosed with low T3 syndrome, which was associated with worse PFS and OS in the rituximab era. It was an independent prognostic factor for PFS and OS, especially for those with IPI 0-2, extranodal sites ≤1 and stage III-IV. Synchronously low FT3 and FT4 had poorer survival outcome compared to only low FT3 and adding criterion of low T3 syndrome improved the prognostic capacity of IPI for predicting PFS and OS in DLBCL. Low T3 syndrome was found to be a strong prognostic predictor in DLBCL.

  16. Prophylactic CNS directed therapy in systemic diffuse large B cell lymphoma.

    PubMed

    Ghose, Abhimanyu; Kundu, Ria; Latif, Tahir

    2014-09-01

    Overall survival in diffuse large B-cell lymphoma (DLBCL) has significantly improved in the last decade, especially after the incorporation of rituximab. Involvement of the central nervous system (CNS) at presentation or at recurrence is an uncommon event, but carries a dismal prognosis with median survival of less than 6 months. Although prophylactic CNS directed therapy is a widely used approach to prevent this complication, randomized clinical trials have been very limited. CNS prophylaxis has inherent toxicities; therefore, identifying the population of patients who would receive most benefit is of utmost importance. From an extensive review of current literature, we report the incidence of CNS relapse in DLBCL and describe the role of CNS prophylaxis in the post-rituximab compared to the pre-rituximab era. We also review the current modalities of CNS prophylaxis and attempt to identify the high-risk patients who would benefit. Lastly, we present a treatment algorithm that defines the role of CNS prophylaxis in the management of patients with DLBCL.

  17. SILAC-Based Quantitative Proteomic Analysis of Diffuse Large B-Cell Lymphoma Patients

    PubMed Central

    Rüetschi, Ulla; Stenson, Martin; Hasselblom, Sverker; Nilsson-Ehle, Herman; Hansson, Ulrika; Fagman, Henrik; Andersson, Per-Ola

    2015-01-01

    Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, is a heterogeneous disease where the outcome for patients with early relapse or refractory disease is very poor, even in the era of immunochemotherapy. In order to describe possible differences in global protein expression and network patterns, we performed a SILAC-based shotgun (LC-MS/MS) quantitative proteomic analysis in fresh-frozen tumor tissue from two groups of DLBCL patients with totally different clinical outcome: (i) early relapsed or refractory and (ii) long-term progression-free patients. We could identify over 3,500 proteins; more than 1,300 were quantified in all patients and 87 were significantly differentially expressed. By functional annotation analysis on the 66 proteins overexpressed in the progression-free patient group, we found an enrichment of proteins involved in the regulation and organization of the actin cytoskeleton. Also, five proteins from actin cytoskeleton regulation, applied in a supervised regression analysis, could discriminate the two patient groups. In conclusion, SILAC-based shotgun quantitative proteomic analysis appears to be a powerful tool to explore the proteome in DLBCL tumor tissue. Also, as progression-free patients had a higher expression of proteins involved in the actin cytoskeleton protein network, such a pattern indicates a functional role in the sustained response to immunochemotherapy. PMID:26060582

  18. Identification of LMO2 transcriptome and interactome in diffuse large B-cell lymphoma

    PubMed Central

    Cubedo, Elena; Gentles, Andrew J.; Huang, Chuanxin; Natkunam, Yasodha; Bhatt, Shruti; Lu, Xiaoqing; Jiang, Xiaoyu; Romero-Camarero, Isabel; Freud, Aharon; Zhao, Shuchun; Bacchi, Carlos E.; Martínez-Climent, Jose A.; Sánchez-García, Isidro; Melnick, Ari

    2012-01-01

    LMO2 regulates gene expression by facilitating the formation of multipartite DNA-binding complexes. In B cells, LMO2 is specifically up-regulated in the germinal center (GC) and is expressed in GC-derived non-Hodgkin lymphomas. LMO2 is one of the most powerful prognostic indicators in diffuse large B-cell (DLBCL) patients. However, its function in GC B cells and DLBCL is currently unknown. In this study, we characterized the LMO2 transcriptome and transcriptional complex in DLBCL cells. LMO2 regulates genes implicated in kinetochore function, chromosome assembly, and mitosis. Overexpression of LMO2 in DLBCL cell lines results in centrosome amplification. In DLBCL, the LMO2 complex contains some of the traditional partners, such as LDB1, E2A, HEB, Lyl1, ETO2, and SP1, but not TAL1 or GATA proteins. Furthermore, we identified novel LMO2 interacting partners: ELK1, nuclear factor of activated T-cells (NFATc1), and lymphoid enhancer-binding factor1 (LEF1) proteins. Reporter assays revealed that LMO2 increases transcriptional activity of NFATc1 and decreases transcriptional activity of LEF1 proteins. Overall, our studies identified a novel LMO2 transcriptome and interactome in DLBCL and provides a platform for future elucidation of LMO2 function in GC B cells and DLBCL pathogenesis. PMID:22517897

  19. Deregulation of COMMD1 Is Associated with Poor Prognosis in Diffuse Large B-cell Lymphoma

    PubMed Central

    Taskinen, Minna; Louhimo, Riku; Koivula, Satu; Chen, Ping; Rantanen, Ville; Holte, Harald; Delabie, Jan; Karjalainen-Lindsberg, Marja-Liisa; Björkholm, Magnus; Fluge, Øystein; Pedersen, Lars Møller; Fjordén, Karin; Jerkeman, Mats; Eriksson, Mikael; Hautaniemi, Sampsa; Leppä, Sirpa

    2014-01-01

    Background Despite improved survival for the patients with diffuse large B-cell lymphoma (DLBCL), the prognosis after relapse is poor. The aim was to identify molecular events that contribute to relapse and treatment resistance in DLBCL. Methods We analysed 51 prospectively collected pretreatment tumour samples from clinically high risk patients treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis with high resolution array comparative genomic hybridization (aCGH) and gene expression microarrays. Major finding was validated at the protein level immunohistochemically in a trial specific tissue microarray series of 70, and in an independent validation series of 146 patients. Results We identified 31 genes whose expression changes were strongly associated with copy number aberrations. In addition, gains of chromosomes 2p15 and 18q12.2 were associated with unfavourable survival. The 2p15 aberration harboured COMMD1 gene, whose expression had a significant adverse prognostic impact on survival. Immunohistochemical analysis of COMMD1 expression in two series confirmed the association of COMMD1 expression with poor prognosis. Conclusion COMMD1 is a potential novel prognostic factor in DLBCLs. The results highlight the value of integrated comprehensive analysis to identify prognostic markers and genetic driver events not previously implicated in DLBCL. Trial Registration ClinicalTrials.gov NCT01502982 PMID:24625556

  20. The potential relevance of the endocannabinoid, 2-arachidonoylglycerol, in diffuse large B-cell lymphoma

    PubMed Central

    Zhang, Jianqing; Medina-Cleghorn, Daniel; Bernal-Mizrachi, Leon; Bracci, Paige M.; Hubbard, Alan; Conde, Lucia; Riby, Jacques; Nomura, Daniel K.; Skibola, Christine F.

    2016-01-01

    Diffuse large B-cell lymphoma is an aggressive, genetically heterogenerous disease and the most common type of non-Hodgkin lymphoma among adults. To gain further insights into the etiology of DLBCL and to discover potential disease-related factors, we performed a serum lipid analysis on a subset of individuals from a population-based NHL case-control study. An untargeted mass-spectrometry-based metabolomics platform was used to analyze serum samples from 100 DLBCL patients and 100 healthy matched controls. Significantly elevated levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), were detected in the serum of DLBCL patients (121%, P < 0.05). In the male controls, elevated 2-AG levels were observed in those who were overweight (BMI ≥ 25 - < 30 kg/m2; 108%, P < 0.01) and obese (BMI ≥ 30 kg/m2; 118%, P < 0.001) compared to those with a BMI < 25 kg/m2. DLBCL cell lines treated with exogenous 2-AG across a range of concentrations, exhibited heterogenous responses: proliferation rates were markedly higher in 4 cell lines by 22%-68% (P < 0.001) and lower in 8 by 20%-75% (P < 0.001). The combined findings of elevated 2-AG levels in DLBCL patients and the proliferative effects of 2-AG on a subset of DLBCL cell lines suggests that 2-AG may play a potential role in the pathogenesis or progression of a subset of DLBCLs. PMID:26973858

  1. Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma.

    PubMed

    Cardenas, Mariano G; Yu, Wenbo; Beguelin, Wendy; Teater, Matthew R; Geng, Huimin; Goldstein, Rebecca L; Oswald, Erin; Hatzi, Katerina; Yang, Shao-Ning; Cohen, Joanna; Shaknovich, Rita; Vanommeslaeghe, Kenno; Cheng, Huimin; Liang, Dongdong; Cho, Hyo Je; Abbott, Joshua; Tam, Wayne; Du, Wei; Leonard, John P; Elemento, Olivier; Cerchietti, Leandro; Cierpicki, Tomasz; Xue, Fengtian; MacKerell, Alexander D; Melnick, Ari M

    2016-09-01

    Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.

  2. Antitumor activity of fucoidan against diffuse large B cell lymphoma in vitro and in vivo.

    PubMed

    Yang, Guang; Zhang, Qianqiao; Kong, Yuanyuan; Xie, Bingqian; Gao, Minjie; Tao, Yi; Xu, Hongwei; Zhan, Fenghuang; Dai, Bojie; Shi, Jumei; Wu, Xiaosong

    2015-11-01

    Fucoidan is one of the major sulfated polysaccharides isolated from brown seaweeds. In this study, we determined the anti-cancer activity of fucoidan on diffuse large B cell lymphoma (DLBCL) cells both in vitro and in vivo. Fucoidan inhibited the growth of DLBCL cells in a dose- and time-dependent manner, and fucoidan treatment provoked G0/G1 cell cycle arrest, which was accompanied by p21 up-regulation and cyclin D1, Cdk4, and Cdk6 down-regulation. Fucoidan also induced caspase-dependent cell apoptosis in DLBCL cell lines and primary DLBCL cell. In addition, fucoidan treatment caused the loss of mitochondrial membrane potential and the release of cytochrome c and apoptosis-inducing factor from the mitochondria into the cytosol. Fucoidan also potentiated the activities of carfilzomib in killing DLBCL cells. Oral administration of fucoidan effectively inhibited tumor growth in xenograft mouse models. Our findings reveal the novel function of fucoidan as an anti-DLBCL agent, which can be used in the clinical treatment of DLBCL.

  3. [REACTIVATION OF TUBERCULOSIS PRESENTING WITH EMPYEMA DUE TO ANTICANCER CHEMOTHERAPY FOR DIFFUSE LARGE B CELL LYMPHOMA].

    PubMed

    Yuba, Tatsuya; Hatsuse, Mayumi; Kodama, Mai; Uda, Sayaka; Yoshimura, Akihiro; Kurisu, Naoko

    2016-04-01

    A 79-year-old man with a history of tuberculosis was found to have chronic empyema in the right lung and was diagnosed with malignant diffuse large-cell lymphoma (Ann Arbor stage IIE). After completion of one course of rituximab plus cyclophosphamide, pirarubicin, vincristine, and prednisolone (R-CHOP) chemotherapy, the patient developed lung abscess and sepsis caused by Streptococcus intermedius. This condition was treated with antimicrobial agents, and chemotherapy was resumed. After the second course, the chemotherapy regimen was continued without prednisolone, and after administration of the third course, a chest wall mass was found in the right lung. An acid-fast bacillus smear test of the abscess aspirate was positive, and Mycobacterium tuberculosis was detected in a polymerase chain reaction assay, leading to a diagnosis of perithoracic tuberculosis. Chemotherapy for the lymphoma was discontinued, and treatment with four oral antitubercular agents was started. This treatment led to remission of perithoracic tuberculosis. In Japan, tuberculous scar and chronic empyema are relatively common findings, and relapse of tuberculosis should always be considered for patients with these findings during chemotherapy and immunosuppressive therapy.

  4. Primary Diffuse Large B-Cell Lymphoma of the Liver in a Patient with Sjogren Syndrome

    PubMed Central

    Gorodetskiy, Vadim; Klapper, Wolfram; Probatova, Natalya; Vasilyev, Vladimir

    2016-01-01

    Sjögren's syndrome (SS) has the highest incidence of malignant lymphoproliferative disorders transformation among autoimmune diseases. We present a case of extranodal high grade lymphoma of the liver in a 52-year-old patient with long history of SS. Lymphoma manifested with sharp significant pain in the right hypochondrium, weakness, and profuse night sweats. Contrast-enhanced computed tomography scan (CT-scan) of the abdomen revealed multiple low density foci with homogeneous structure and clear contours in both lobes of the liver. Histologically, proliferation of medium sized lymphoma cells with round-oval and slightly irregular nuclei with fine chromatin was shown. Immunohistochemical and molecular features of the tumors allowed diagnosis of diffuse large B-cell lymphoma (DLBCL). To exclude secondary liver lesion by non-Hodgkin lymphoma, chest and small pelvis CT-scan, endoscopy of upper and lower gastrointestinal tract and study of bone marrow were performed. After 8 cycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the complete remission was achieved, which persists after 45 months of follow-up. Primary hepatic lymphomas are extremely rare, and previously only low-grade hepatic lymphomas have been described in SS. To our knowledge, the patient described here represents the first reported case of DLBCL with primary liver involvement in SS. PMID:26998372

  5. Diffuse Large B Cell Lymphoma Cell Line U-2946: Model for MCL1 Inhibitor Testing

    PubMed Central

    Quentmeier, Hilmar; Drexler, Hans G.; Hauer, Vivien; MacLeod, Roderick A. F.; Pommerenke, Claudia; Uphoff, Cord C.; Zaborski, Margarete; Berglund, Mattias

    2016-01-01

    Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma worldwide. We describe the establishment and molecular characteristics of the DLBCL cell line U-2946. This cell line was derived from a 52-year-old male with DLBCL. U-2946 cells carried the chromosomal translocation t(8;14) and strongly expressed MYC, but not the mature B-cell lymphoma associated oncogenes BCL2 and BCL6. Instead, U-2946 cells expressed the antiapoptotic BCL2 family member MCL1 which was highly amplified genomically (14n). MCL1 amplification is recurrent in DLBCL, especially in the activated B cell (ABC) variant. Results of microarray expression cluster analysis placed U-2946 together with ABC-, but apart from germinal center (GC)-type DLBCL cell lines. The 1q21.3 region including MCL1 was focally coamplified with a short region of 17p11.2 (also present at 14n). The MCL1 inhibitor A-1210477 triggered apoptosis in U-2946 (MCL1pos/BCL2neg) cells. In contrast to BCL2pos DLBCL cell lines, U-2946 did not respond to the BCL2 inhibitor ABT-263. In conclusion, the novel characteristics of cell line U-2946 renders it a unique model system to test the function of small molecule inhibitors, especially when constructing a panel of DLBCL cell lines expressing broad combinations of antiapoptotic BCL2-family members. PMID:27907212

  6. Diffuse Large B Cell Lymphoma Cell Line U-2946: Model for MCL1 Inhibitor Testing.

    PubMed

    Quentmeier, Hilmar; Drexler, Hans G; Hauer, Vivien; MacLeod, Roderick A F; Pommerenke, Claudia; Uphoff, Cord C; Zaborski, Margarete; Berglund, Mattias; Enblad, Gunilla; Amini, Rose-Marie

    2016-01-01

    Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma worldwide. We describe the establishment and molecular characteristics of the DLBCL cell line U-2946. This cell line was derived from a 52-year-old male with DLBCL. U-2946 cells carried the chromosomal translocation t(8;14) and strongly expressed MYC, but not the mature B-cell lymphoma associated oncogenes BCL2 and BCL6. Instead, U-2946 cells expressed the antiapoptotic BCL2 family member MCL1 which was highly amplified genomically (14n). MCL1 amplification is recurrent in DLBCL, especially in the activated B cell (ABC) variant. Results of microarray expression cluster analysis placed U-2946 together with ABC-, but apart from germinal center (GC)-type DLBCL cell lines. The 1q21.3 region including MCL1 was focally coamplified with a short region of 17p11.2 (also present at 14n). The MCL1 inhibitor A-1210477 triggered apoptosis in U-2946 (MCL1pos/BCL2neg) cells. In contrast to BCL2pos DLBCL cell lines, U-2946 did not respond to the BCL2 inhibitor ABT-263. In conclusion, the novel characteristics of cell line U-2946 renders it a unique model system to test the function of small molecule inhibitors, especially when constructing a panel of DLBCL cell lines expressing broad combinations of antiapoptotic BCL2-family members.

  7. Stress-induced DNA damage: a case study in diffuse large B-cell lymphoma

    PubMed Central

    Nicasio-Collazo, Luz Adriana; Delgado-González, Alexandra; Castañeda-Priego, Ramón; Hernández-Lemus, Enrique

    2014-01-01

    DNA damage is one of the mechanisms of mutagenesis. Sequence integrity may be affected by the action of thermal changes, chemical agents, both endogenous and exogenous, and other environmental issues. Abnormally high mutation rates are referred to as genomic instability: a phenomenon closely related to the onset of cancer. Mutant genotypes may be able to confer some kind of selective advantage on subclonal cell populations, leading them to multiply until dominance in a localized tissue environment that later becomes the tumour. Cellular stress, especially that of oxidative and ionic nature, is a recognized trigger for DNA-damaging processes. A physico-chemical model has shown that high hysteresis rates in DNA denaturation curves may be indicative of dissipative processes inducing DNA damage, thus potentially leading to uncontrolled mutagenesis and genome instability. We here study selectively to what extent this phenomenon may occur by analysing the sequence length and composition effects on the thermodynamic behaviour and the presence of hysteresis in pressure-driven DNA denaturation; pronounced hysteresis in the denaturation/renaturation curves may indicate thermal susceptibility to DNA damage. In particular, we consider highly mutated regions of the genome characterized in diffuse large B-cell lymphoma on a recent whole exome next-generation sequencing effort. PMID:25209404

  8. Beyond RCHOP: A Blueprint for Diffuse Large B Cell Lymphoma Research.

    PubMed

    Nowakowski, Grzegorz S; Blum, Kristie A; Kahl, Brad S; Friedberg, Jonathan W; Baizer, Lawrence; Little, Richard F; Maloney, David G; Sehn, Laurie H; Williams, Michael E; Wilson, Wyndham H; Leonard, John P; Smith, Sonali M

    2016-12-01

    Diffuse large B cell lymphoma (DLBCL) comprises multiple molecular and biological subtypes, resulting in a broad range of clinical outcomes. With standard chemoimmunotherapy, there remains an unacceptably high treatment failure rate in certain DLBCL subsets: activated B cell (ABC) DLBCL, double-hit lymphoma defined by the dual translocation of MYC and BCL2, dual protein-expressing lymphomas defined by the overexpression of MYC and BCL2, and older patients and those with central nervous system involvement. The main research challenges for DLBCL are to accurately identify molecular subsets and to determine if specific chemotherapy platforms and targeted agents offer differential benefit. The ultimate goal should be to maximize initial cure rates to improve long-term survival while minimizing toxicity. In particular, a frontline trial should focus on biologically defined risk groups not likely to be cured with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP). An additional challenge is to develop effective and personalized strategies in the relapsed setting, for which there is no current standard other than autologous stem cell transplantation, which benefits a progressively smaller proportion of patients. Relapsed/refractory DLBCL is the ideal setting for testing novel agents and new biomarker tools and will require a national call for biopsies to optimize discovery in this setting. Accordingly, the development of tools with both prognostic and predictive utility and the individualized application of new therapies should be the main priorities. This report identifies clinical research priorities for critical areas of unmet need in this disease.

  9. Pterostilbene induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma cells

    PubMed Central

    Kong, Yuanyuan; Chen, Gege; Xu, Zhijian; Yang, Guang; Li, Bo; Wu, Xiaosong; Xiao, Wenqin; Xie, Bingqian; Hu, Liangning; Sun, Xi; Chang, Gaomei; Gao, Minjie; Gao, Lu; Dai, Bojie; Tao, Yi; Zhu, Weiliang; Shi, Jumei

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). Pterostilbene, a natural dimethylated analog of resveratrol, has been shown to possess diverse pharmacological activities, including anti-inflammatory, antioxidant and anticancer properties. However, to the best of our knowledge, there has been no study of the effects of pterostilbene upon hematological malignancies. Herein, we report the antitumor activity and mechanism of pterostilbene against DLBCL cells both in vitro and in vivo. We found that pterostilbene treatment resulted in a dose-dependent inhibition of cell viability. In addition, pterostilbene exhibited a strong cytotoxic effect, as evidenced not only by reductions of mitochondrial membrane potential (MMP) but also by increases in cellular apoptotic index and reactive oxygen species (ROS) levels, leading to arrest in the S-phase of the cell cycle. Furthermore, pterostilbene treatment directly up-regulated p-p38MAPK and down-regulated p-ERK1/2. In vivo, intravenous administration of pterostilbene inhibited tumor development in xenograft mouse models. Overall, the results suggested that pterostilbene is a potential anti-cancer pharmaceutical against human DLBCL by a mechanism involving the suppression of ERK1/2 and activation of p38MAPK signaling pathways. PMID:27869173

  10. Central nervous system prophylaxis in diffuse large B-cell lymphoma.

    PubMed

    Zahid, Mohammad Faizan; Khan, Nadia; Hashmi, Shahrukh K; Kizilbash, Sani Haider; Barta, Stefan K

    2016-08-01

    Central nervous system (CNS) involvement with diffuse large B-cell lymphoma (DLBCL) is a relatively uncommon manifestation; with most cases of CNS involvement occuring during relapse after primary therapy. CNS dissemination typically occurs early in the disease course and is most likely present subclinically at the time of diagnosis in many patients who later relapse in the CNS. CNS relapse in these patients is associated with poor outcomes. Based on a CNS relapse rate of 5% in DLBCL and weighing the benefits against the toxicities, universal application of CNS prophylaxis is not justified. The introduction of rituximab has significantly reduced the incidence of CNS relapse in DLBCL. Different studies have employed other agents for CNS prophylaxis, such as intrathecal chemotherapy and high-dose systemic agents with sufficient CNS penetration. If CNS prophylaxis is to be given, it should be preferably administered during primary chemotherapy. However, there is no strong evidence that supports any single approach for CNS prophylaxis. In this review, we outline different strategies of administering CNS prophylaxis in DLBCL patients reported in literature and discuss their advantages and drawbacks.

  11. Serum Cystatin C as a Biomarker in Diffuse Large B-Cell Lymphoma.

    PubMed

    Hammouda, Nada E; Salah El-Din, Manal A; El-Shishtawy, Mamdouh M; El-Gayar, Amal M

    2017-03-08

    Elevated serum levels of cystatin C are found to be related to poor outcome and metastatic potential of some malignant disorders. To evaluate the clinical prominence of serum cystatin C in diffuse large B-cell lymphoma (DLBCL), blood samples were obtained from 58 patients at the time of diagnosis and paired blood samples were obtained from 22 patients at the time of remission. Also, serum cystatin C level was measured in matched healthy controls. Serum cystatin C levels were significantly more elevated in DLBCL patients than in controls (p < 0.0001). Furthermore, paired-sample analysis revealed that pretreatment cystatin C levels were reduced significantly in patients who achieved remission after therapy (p = 0.016). High serum cystatin C levels were correlated with age over 60 years (p = 0.049), extra-nodal involvement (p = 0.005) and with high serum lactate dehydrogenase (LDH) (p < 0.013). Elevated serum cystatin C levels were associated with extra-nodal involvement and they were significantly reduced to normal range after the remission. However, Kaplan-Meier curves revealed no survival difference in the pretreatment serum cystatin C levels. Therefore, serum cystatin C may be a novel biomarker that reflects tumor burden in DLBCL but bears no prognostic significance regarding survival.

  12. Imaging in diffusing media with a neural net formulation: a problem in large-scale computation

    NASA Astrophysics Data System (ADS)

    Schlereth, Fred H.; Fossaceca, John A.; Keckler, Andrew D.; Barbour, Randall L.

    1992-05-01

    Attempts to recover images from objects which diffuse radiation pose an especially challenging problem in terms of defining a suitable reconstruction algorithm and with regard to identifying an appropriate computing environment for efficient processing. In this paper we consider both issues and, in particular, describe results of an algebraic technique for imaging the interior of objects which diffuse penetrating radiation using a new multicomputer environment. Two important issues which arise when considering the numerical solution of ultra large problems are the numerical precision achieved and the overall computing efficiency. Our interest in this problem concerns the possibility of obtaining 3-D optical images of tissue which could identify the availability of oxygen by evaluating oxygen- dependent changes in the near infrared spectrum of hemoglobin. These studies were motivated by recent reports from our group and others, which showed promising results for imaging in dense scattering media given only diffusely scattered signals. In our model we assume the use of an NIR laser to provide the input radiation and suitable detectors to measure both transmission and backscatter. In our present work we assume a simple Markov process model for the way in which the energy travels in the medium, but it should be noted that the reconstruction technique we propose can use any model, including nonlinear as well as linear effects, and higher order processes. Current simulations are in 2-D but the methods are easily extended to 3-D. The algorithms we propose are more closely related to algebraic reconstruction algorithms such as ART, SIRT, and SART than to algorithms based on the Born and Rytov approximations such as used for tomographic imaging with diffracting sources. Our algorithms are a significant departure from those based on these standard algebraic methods. We assume only a probabilistic knowledge of the path of the radiation, and minimal knowledge of the absorption

  13. NASA/DOD Aerospace Knowledge Diffusion Research Project. Paper 59: Japanese Technological Innovation. Implications for Large Commercial Aircraft and Knowledge Diffusion

    NASA Technical Reports Server (NTRS)

    Pinelli, Thomas E.; Barclay, Rebecca O.; Kotler, Mindy L.

    1997-01-01

    This paper explores three factors-public policy, the Japanese (national) innovation system, and knowledge-that influence technological innovation in Japan. To establish a context for the paper, we examine Japanese culture and the U.S. and Japanese patent systems in the background section. A brief history of the Japanese aircraft industry as a source of knowledge and technology for other industries is presented. Japanese and U.S. alliances and linkages in three sectors-biotechnology, semiconductors, and large commercial aircraft (LCA)-and the importation, absorption, and diffusion of knowledge and technology are examined next. The paper closes with implications for diffusing knowledge and technology, U.S. public policy, and LCA.

  14. Mutational and structural analysis of diffuse large B-cell lymphoma using whole genome sequencing | Office of Cancer Genomics

    Cancer.gov

    Abstract: Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous cancer comprising at least two molecular subtypes that differ in gene expression and distribution of mutations. Recently, application of genome/exome sequencing and RNA-seq to DLBCL has revealed numerous genes that are recurrent targets of somatic point mutation in this disease.

  15. Genomic imbalances during transformation from follicular lymphoma to diffuse large B-cell lymphoma.

    PubMed

    Berglund, Mattias; Enblad, Gunilla; Thunberg, Ulf; Amini, Rose-Marie; Sundström, Christer; Roos, Göran; Erlanson, Martin; Rosenquist, Richard; Larsson, Catharina; Lagercrantz, Svetlana

    2007-01-01

    Follicular lymphoma is commonly transformed to a more aggressive diffuse large B-cell lymphoma (DLBCL). In order to provide molecular characterization of this histological and clinical transformation, comparative genomic hybridization was applied to 23 follicular lymphoma and 35 transformed DLBCL tumors from a total of 30 patients. The results were also compared with our published findings in de novo DLBCL. Copy number changes were detected in 70% of follicular lymphoma and in 97% of transformed DLBCL. In follicular lymphoma, the most common alterations were +18q21 (33%), +Xq25-26 (28%), +1q31-32 (23%), and -17p (23%), whereas transformed DLBCL most frequently exhibited +Xq25-26 (36%), +12q15 (29%), +7pter-q22 (25%), +8q21 (21%), and -6q16-21(25%). Transformed DLBCL showed significantly more alterations as compared to follicular lymphoma (P=0.0001), and the alterations -6q16-21 and +7pter-q22 were only found in transformed DLBCL but not in follicular lymphoma (P=0.02). Alterations involving +13q22 were significantly less frequent, whereas -4q13-21 was more common in transformed as compared to de novo DLBCL (P=0.01 and P=0.02, respectively). Clinical progression from follicular lymphoma to transformed DLBCL is on the genetic level associated with acquisition of increasing number of genomic copy number changes, with non-random involvement of specific target regions. The findings support diverse genetic background between transformed and de novo DLBCL.

  16. Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma.

    PubMed

    Hansen, Jakob Werner; Garde, Christian; Asmar, Fazila; Tholstrup, Dorte; Kristensen, Søren Sommer; Munch-Petersen, Helga D; Ralfkiaer, Elisabeth; Brown, Peter; Grønbaek, Kirsten; Kristensen, Lasse Sommer; Wedge, Eileen

    2017-04-05

    Global hypomethylation has been linked to disease progression in several cancers, but has not been reported for Diffuse Large B Cell Lymphoma (DLBCL). This study aimed to assess global methylation in DLBCL and describe its prognostic value. Mean LINE1 methylation, a validated surrogate measure for global methylation, was measured in DNA from 67 tumor biopsies. Additionally, cell-free circulating DNA (cfDNA) in plasma samples from 74 patients was tested to assess the feasibility of global hypomethylation as a biomarker in liquid biopsies. LINE1 methylation was assessed using a commercially available kit, based on pyrosequencing of PCR amplified bisulfite-treated DNA. Global hypomethylation was detected in a subset of cases and was associated with poor overall survival in both tumor biopsies (P=0.001) and cfDNA (P=0.009). It was the strongest risk factor in multivariate analysis in both biopsies (HR: 10.65, CI: 2.03-55.81, P=0.005) and cfDNA (HR: 11.87, CI: 2.80-50.20, P=0.001), outperforming conventional clinical risk factors. Finally, hierarchical cluster analyses were performed for the cfDNA samples using previously published gene-specific methylation data. This analysis shows that global hypomethylation co-occurs with other epigenetic abnormalities, including DAPK1 promoter hypermethylation. In conclusion, we have shown that global hypomethylation is strongly associated with poor survival in DLBCL both when present in tumor biopsy DNA and when detected in plasma cfDNA, and has potential for clinical application as a prognostic biomarker. This article is protected by copyright. All rights reserved.

  17. Hepatitis C virus and diffuse large B-cell lymphoma: Pathogenesis, behavior and treatment

    PubMed Central

    Visco, Carlo; Finotto, Silvia

    2014-01-01

    A significant association between hepatitis C virus (HCV) infection and B-cell lymphoma has been reported by epidemiological studies, most of them describing a strong relationship between indolent lymphomas and HCV. Furthermore, the curative potential of antiviral therapy on HCV related indolent lymphomas supports a specific role for the virus in lymphomagenesis. These observations are reinforced by numerous laboratory experiments that led to several hypothetical models of B-cell transformation by HCV. Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype in the western countries, has been associated to HCV infection despite its aggressive nature. This association seems particularly prominent in some geographical areas. Clinical presentation of HCV-associated DLBCL has consistently been reported to differ from the HCV-negative counterpart. Nevertheless, histopathology, tolerance to standard-of-care chemo-immunotherapy (R-CHOP or CHOP-like regimens) and final outcome of HCV-positive DLBCL patients is still matter of debate. Addition of rituximab has been described to enhance viral replication but the probability of severe hepatic complications remains low, with some exceptions (i.e., hepatitis B virus or immune immunodeficiency virus co-infected patients, presence of grade > 2 transaminases elevation, cirrhosis or hepatocarcinoma). HCV viral load in this setting is not necessarily directly associated with liver damage. Overall, treatment of HCV associated DLBCL should be performed in an interdisciplinary approach with hepatologists and hematologists with close monitoring of liver function. Available reports reveal that the final outcome of HCV-positive DLBCL that receive standard immunochemotherapy is not inferior to their HCV-negative counterpart. This review summarizes data on epidemiology, pathogenesis and therapeutic approach on HCV-associated DLBCL. Several issues that are matter of debate like clinical management of patients with transaminase

  18. Diffuse large B-cell lymphoma genotyping on the liquid biopsy.

    PubMed

    Rossi, Davide; Diop, Fary; Spaccarotella, Elisa; Monti, Sara; Zanni, Manuela; Rasi, Silvia; Deambrogi, Clara; Spina, Valeria; Bruscaggin, Alessio; Favini, Chiara; Serra, Roberto; Ramponi, Antonio; Boldorini, Renzo; Foa', Robin; Gaidano, Gianluca

    2017-01-17

    Accessible and real-time genotyping for diagnostic, prognostic or treatment purposes is increasingly impelling in diffuse large B-cell lymphoma (DLBCL). Cell-free DNA (cfDNA) is shed into the blood by tumor cells undergoing apoptosis and can be used as source of tumor DNA for the identification of DLBCL mutations, clonal evolution, and genetic mechanisms of resistance. Here we aimed at tracking the basal DLBCL genetic profile and its modification upon treatment using plasma cfDNA. Ultra-deep targeted next generation sequencing of pre-treatment plasma cfDNA from DLBCL patients correctly discovered DLBCL-associated mutations that were represented in >20% of the alleles of the tumor biopsy with a >90% sensitivity and a ~100% specificity. Plasma cfDNA genotyping allowed also to recover mutations that were undetectable in the tissue biopsy conceivably because, due to spatial tumor heterogeneity, they were restricted to clones that were anatomically distant from the biopsy site. Longitudinal analysis of plasma samples collected under R-CHOP chemotherapy showed a rapid clearance of DLBCL mutations from cfDNA among responding patients. Conversely, among patients resistant to R-CHOP, basal DLBCL mutations did not disappear from cfDNA. In addition, among treatment-resistant patients, new mutations were acquired in cfDNA that marked resistant clones selected during the clonal evolution. These results demonstrate that cfDNA genotyping of DLBCL is as accurate as genotyping of the diagnostic biopsy to detect clonally represented somatic tumor mutations and is a real-time and non-invasive approach to track clonal evolution and emergence of treatment resistant clones.

  19. Immunohistochemical and Molecular Characteristics with Prognostic Significance in Diffuse Large B-Cell Lymphoma

    PubMed Central

    Bellas, Carmen; García, Diego; Vicente, Yolanda; Kilany, Linah; Abraira, Victor; Navarro, Belen; Provencio, Mariano; Martín, Paloma

    2014-01-01

    Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with marked biologic heterogeneity. We analyzed 100 cases of DLBCL to evaluate the prognostic value of immunohistochemical markers derived from the gene expression profiling-defined cell origin signature, including MYC, BCL2, BCL6, and FOXP1 protein expression. We also investigated genetic alterations in BCL2, BCL6, MYC and FOXP1 using fluorescence in situ hybridization and assessed their prognostic significance. BCL6 rearrangements were detected in 29% of cases, and BCL6 gene alteration (rearrangement and/or amplification) was associated with the non-germinal center B subtype (non-GCB). BCL2 translocation was associated with the GCB phenotype, and BCL2 protein expression was associated with the translocation and/or amplification of 18q21. MYC rearrangements were detected in 15% of cases, and MYC protein expression was observed in 29% of cases. FOXP1 expression, mainly of the non-GCB subtype, was demonstrated in 37% of cases. Co-expression of the MYC and BCL2 proteins, with non-GCB subtype predominance, was observed in 21% of cases. We detected an association between high FOXP1 expression and a high proliferation rate as well as a significant positive correlation between MYC overexpression and FOXP1 overexpression. MYC, BCL2 and FOXP1 expression were significant predictors of overall survival. The co-expression of MYC and BCL2 confers a poorer clinical outcome than MYC or BCL2 expression alone, whereas cases negative for both markers had the best outcomes. Our study confirms that DLBCL, characterized by the co-expression of MYC and BCL2 proteins, has a poor prognosis and establishes a significant positive correlation with MYC and FOXP1 over-expression in this entity. PMID:24887414

  20. Unusual Presentation of Diffuse Large B-Cell Lymphoma With Splenic Infarcts

    PubMed Central

    Kumar, Vivek; Soni, Parita; Dave, Vishangi; Harris, Jonathan

    2017-01-01

    A 67-year-old man presented with a 3-day history of abdominal pain, fever, and significant weight loss over 2 months. Physical examination revealed left upper quadrant tenderness, hepatomegaly, splenomegaly, and bilateral pitting edema but peripheral lymphadenopathy was absent. Laboratory tests showed anemia, thrombocytopenia, elevated prothrombin time (PT), partial thromboplastin time (PTT), and increased lactate dehydrogenase (LDH). PTT was corrected completely in mixing study. Further workup for the cause of coagulopathy revealed decreased levels of all clotting factors except factor VIII and increase fibrinogen levels, which ruled out disseminated intravascular coagulation (DIC). Flow cytometry of peripheral blood was normal. Contrast-enhanced computed tomography (CECT) revealed splenomegaly with multiple splenic infarcts without any mediastinal or intraabdominal lymphadenopathy. Further investigations for infective endocarditis (blood cultures and transthoracic echocardiography) and autoimmune disorders (ANA, dsDNA, RA factors) were negative. The patient received treatment for sepsis empirically without any significant clinical improvement. The diagnosis remained unclear despite extensive workup and liver biopsy was conducted due to high suspicion of granulomatous diseases. However, the liver biopsy revealed high-grade diffuse large B-cell lymphoma (DLBCL). Unfortunately, patient died shortly after the diagnosis. Here we report a case of high-grade DLBCL with hepatosplenomegaly and splenic infarcts in the absence of any lymphadenopathy or focal lesions. This case highlights the fact that unusually lymphoma can present in the absence of lymphadenopathy or mass lesion mimicking autoimmune and granulomatous disorders. The diagnosis in these cases can only be made on histology, and hence the threshold for biopsy should be low in patients with unclear presentations and multiorgan involvement. PMID:28203580

  1. On the Fermi Large Area Telescope Surplus of Diffuse Galactic Gamma-Ray Emission

    NASA Astrophysics Data System (ADS)

    Völk, H. J.; Berezhko, E. G.

    2013-11-01

    Recent observations of diffuse Galactic γ-ray emission (DGE) by the Fermi Large Area Telescope (Fermi-LAT) have shown significant deviations, above a few GeV to about 100 GeV, from DGE models that use the GALPROP code for the propagation of cosmic ray (CR) particles outside their sources in the Galaxy and their interaction with the target distributions of the interstellar gas and radiation fields. The surplus of radiation observed is most pronounced in the inner Galaxy, where the concentration of CR sources is strongest. The present study investigates this "Fermi-LAT Galactic Plane Surplus" by estimating the γ-ray emission from the sources themselves, which is disregarded in the above DGE models. It is shown that the expected hard spectrum of CRs, still confined in their sources (source cosmic rays, SCRs), can indeed explain this surplus. The method is based on earlier studies regarding the so-called EGRET GeV excess, which by now is generally interpreted as an instrumental effect. The contribution from SCRs is also predicted to increasingly exceed the DGE models above 100 GeV, up to γ-ray energies of about 10 TeV, where the corresponding surplus exceeds the hadronic part of the DGE by about one order of magnitude. Above such energies, the emission surplus should decrease again with energy due to the finite lifetime of the assumed supernova remnant sources. Observations of the DGE in the inner Galaxy at 15 TeV with the ground-based Milagro γ-ray detector and, at TeV energies, with the ARGO-YBJ detector are interpreted to provide confirmation of a significant SCR contribution to the DGE.

  2. Whole-exome and transcriptome sequencing of refractory diffuse large B-cell lymphoma

    PubMed Central

    Park, Ha Young; Lee, Seung-Bok; Yoo, Hae-Yong; Kim, Seok-Jin; Kim, Won-Seog; Kim, Jong-Il; Ko, Young-Hyeh

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although rituximab therapy improves clinical outcome, some patients develop resistant DLBCL; however, the genetic alterations in these patients are not well documented. To identify the genetic background of refractory DLBCL, we conducted whole-exome sequencing and transcriptome sequencing for six patients with refractory and seven with responsive DLBCL. The average numbers of pathogenic somatic single nucleotide variants and indels in coding regions were 71 in refractory patients (range 28–120) and 38 (range 19–66) in responsive patients. Missense mutations of TP53 were exclusive in 50% (3/6) of refractory patients and involved the DNA-binding domain of TP53. All missense mutations of TP53 were accompanied by copy number deletions. RAB11FIP5, PRKCB, PRDM15, FNBP4, AHR, CEP128, BRE, DHX16, MYO6, and NMT1 mutations were recurrent in refractory patients. MYD88, B2M, SORCS3, and WDFY3 mutations were more frequent in refractory patients than in responsive patients. REL–BCL11A fusion was found in two refractory patients; one had both fusion and copy number gain. Recurrent copy gains of POU2AF1, SLC1A4, REL11, FANCL, CACNA1D, TRRAP, and CUX1 with significantly increased average expression were found in refractory patients. The expression profile revealed enriched gene sets associated with treatment resistance, including oxidative phosphorylation and ATP-binding cassette transporters. In conclusion, this study integrated both genomic and transcriptomic alterations associated with refractory DLBCL and found several treatment-resistance alterations that may contribute to refractoriness. PMID:27835906

  3. MicroRNA-142 is mutated in about 20% of diffuse large B-cell lymphoma

    PubMed Central

    Kwanhian, Wiyada; Lenze, Dido; Alles, Julia; Motsch, Natalie; Barth, Stephanie; Döll, Celina; Imig, Jochen; Hummel, Michael; Tinguely, Marianne; Trivedi, Pankaj; Lulitanond, Viraphong; Meister, Gunter; Renner, Christoph; Grässer, Friedrich A

    2012-01-01

    MicroRNAs (miRNAs) are short 18–23 nucleotide long noncoding RNAs that posttranscriptionally regulate gene expression by binding to mRNA. Our previous miRNA profiling of diffuse large B-cell lymphoma (DLBCL) revealed a mutation in the seed sequence of miR-142-3p. Further analysis now showed that miR-142 was mutated in 11 (19.64%) of the 56 DLBCL cases. Of these, one case had a mutation in both alleles, with the remainder being heterozygous. Four mutations were found in the mature miR-142-5p, four in the mature miR-142-3p, and three mutations affected the miR-142 precursor. Two mutations in the seed sequence redirected miR-142-3p to the mRNA of the transcriptional repressor ZEB2 and one of them also targeted the ZEB1 mRNA. However, the other mutations in the mature miR-142-3p did not influence either the ZEB1 or ZEB2 3′ untranslated region (3′ UTR). On the other hand, the mutations affecting the seed sequence of miR-142-3p resulted in a loss of responsiveness in the 3′ UTR of the known miR-142-3p targets RAC1 and ADCY9. In contrast to the mouse p300 gene, the human p300 gene was not found to be a target for miR-142-5p. In one case with a mutation of the precursor, we observed aberrant processing of the miR-142-5p. Our data suggest that the mutations in miR-142 probably lead to a loss rather than a gain of function. This is the first report describing mutations of a miRNA gene in a large percentage of a distinct lymphoma subtype. PMID:23342264

  4. Large Thermal Diffusivity Database Reveals a New Mechanism for Heat Transport in Geomaterials: Diffusion of IR-Polaritons Substantially Augments Phonon-Phonon Scattering

    NASA Astrophysics Data System (ADS)

    Branlund, J. M.; Hofmeister, A.; Dong, J.

    2013-12-01

    Over the course of several years, we have measured heat transport to high temperatures for a large number (ca. 200) of minerals, rocks, glasses and melts using laser flash analysis which eliminates systematic errors (contact losses and boundary-to-boundary radiative transfer gains) that limit utility of conventional, contact techniques. The database is large enough to elucidate patterns. For most samples and particularly for our >60 non-metallic, large single-crystals, >30 glasses and >12 polycrystals, we show that thermal diffusivity is consistently represented by D(T) =F/T ^G + HT, permitting confident extrapolation from conditions in the laboratory to those in the mantle. The two distinct temperature terms describing D(T) suggest that two microscopic mechanisms of conduction exist in the electrical insulators explored. We propose that phonon scattering (the F/T^G term) sums with radiative diffusion of infrared (IR) light in the form of polaritons (the HT term). Speeds near that of sound over unit cell scale lengths exist for the polariton mechanism due to phonon-photon coupling, thereby distinguishing this proposed mechanism from high frequency diffusive radiative transfer which travels near the speed of light, and only is important following transient heating. For 63 single-crystals and many glasses unaffected by disordering or reconstructive phase transitions, G ranges from 0.3 to 2, depending on structure, and H is ~0.0001/ K, and so HT crosses F/T^G by ~1300 K (for most oxides), meaning that radiative diffusion of IR light is more important than phonon scattering inside the Earth. Importantly, the increase in heat transport due to elevated temperature is augmented by the increase due to high P inside planets, providing stability against convection. The popular view of a vigorously convecting interior needs revisiting, given known feedback in the temperature equation and the large size of the HT term. To understand the microscopic basis of HT term, we re

  5. Acculturation, alcohol consumption and AIDS-related risky sexual behavior among African American women.

    PubMed

    Hines, A M; Snowden, L R; Graves, K L

    1998-01-01

    The present study examined the relationship between acculturation, alcohol consumption and AIDS-related risky sexual behavior in a national probability sample of 533 African American women. Results indicated that women who were the heaviest drinkers were also the least acculturated. However, women most likely to engage in risky sexual behavior, including having multiple partners, being nonmonogamous or in a nonmonogamous relationship, and being nonmonogamous or in a nonmonogamous relationship and not using a condom consistently, were high in acculturation rather than low. Alcohol use proved related to risky sexual behavior when considered in conjunction with respondents' level of acculturation. Women at risk for contracting AIDS were not low acculturated African American women who drank heavily, but high acculturated African American women. Findings from this study extend our understanding of risk and contain implications for research and prevention efforts in the area of alcohol use and AIDS-related sexual behavior among African American women.

  6. Mirtazapine and mefloquine therapy for non-AIDS-related progressive multifocal leukoencephalopathy.

    PubMed

    Epperla, Narendranath; Medina-Flores, Rafael; Mazza, Joseph J; Yale, Steven H

    2014-12-01

    Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the human nervous system caused by the JC virus. We report what is, to the best of our knowledge, the second reported case using a combination of mefloquine and mirtazapine in a patient with non-AIDS-related PML with a good clinical outcome. Conversely, the recent trial of mefloquine in 21 patients with AIDS and 3 without AIDS failed to show a reduction of JC viral DNA levels in the cerebral spinal fluid. However, the positive clinical response seen in our patient after the initiation of this combination therapy suggests that further studies in the form of randomized controlled trials for the treatment of non-AIDS-related PML are warranted.

  7. Social disparities, communication inequalities, and HIV/AIDS-related knowledge and attitudes in India.

    PubMed

    Ackerson, Leland K; Ramanadhan, Shoba; Arya, Monisha; Viswanath, Kasisomayajula

    2012-10-01

    Promoting awareness, increasing knowledge, and eliminating stigma is important for stopping the spread of HIV/AIDS. The relation of social determinants and communication inequalities with HIV/AIDS-related cognitive processes has not been studied previously in India. Gender-stratified Poisson regression models of 123,459 women and 73,908 men in the 2005-2006 National Family Health Survey were used to calculate relative risk estimates and 95% confidence intervals for these associations. Results indicated that there are significant inequalities in mass media use among different social classes. Education and wealth are strongly and positively associated with awareness of HIV/AIDS and knowledge about prevention and transmission of AIDS and negatively associated with HIV/AIDS-related stigma. These associations attenuated when use of various mass media types were added to the models with television showing the strongest effect. Mass media may be helpful in reducing social disparities in HIV/AIDS outcomes.

  8. The Spectrum of the Isotropic Diffuse Gamma-Ray Emission Derived From First-Year Fermi Large Area Telescope Data

    SciTech Connect

    Abdo, A. A.

    2011-08-19

    We report on the first Fermi Large Area Telescope (LAT) measurements of the so-called 'extra-galactic' diffuse {gamma}-ray emission (EGB). This component of the diffuse {gamma}-ray emission is generally considered to have an isotropic or nearly isotropic distribution on the sky with diverse contributions discussed in the literature. The derivation of the EGB is based on detailed modelling of the bright foreground diffuse Galactic {gamma}-ray emission (DGE), the detected LAT sources and the solar {gamma}-ray emission. We find the spectrum of the EGB is consistent with a power law with differential spectral index {gamma} = 2.41 {+-} 0.05 and intensity, I(> 100 MeV) = (1.03 {+-} 0.17) x 10{sup -5} cm{sup -2} s{sup -1} sr{sup -1}, where the error is systematics dominated. Our EGB spectrum is featureless, less intense, and softer than that derived from EGRET data.

  9. Trends in AIDS incidence and AIDS-related mortality in British Columbia between 1981 and 2013

    PubMed Central

    Lima, Viviane D.; Lourenço, Lillian; Yip, Benita; Hogg, Robert S.; Phillips, Peter; Montaner, Julio S.G.

    2015-01-01

    Background Appropriate use of highly active antiretroviral therapy (HAART) can markedly decrease the risk of progression to acquired immunodeficiency syndrome (AIDS) and of premature mortality. We aimed to characterize the trends between 1981 and 2013 in AIDS-defining illnesses (ADIs) and in the number AIDS-related deaths in British Columbia (BC), Canada. Methods We included data of 3550 HIV-positive individuals, aged 19 years or older, from different administrative databases in BC. We estimated the relative risk of developing an ADI over time using a Negative Binomial model, and we investigated trends in the percentage of all deaths associated with AIDS using generalized additive models. Findings The number of ADIs has decreased dramatically to its lowest level in 2013. The peak of the AIDS epidemic in BC happened in 1994 with 696 ADIs being reported (rate 42 ADIs per 100 person-years). Since 1997, the number of ADIs decreased from 253 (rate 7 per 100 person-years) to 84 cases in 2013 (rate 1 per 100 person-years) (p-value equals to zero for the trend in the number of ADIs). We have also shown that out of 22 ADIs considered, only PCP maintained its prominent ranking (albeit with much reduced overall prevalence). Finally, we observed that over time very few deaths were related to AIDS-related causes, especially in the most recent years. Interpretation We showed that the number of new ADIs and AIDS-related mortality have been decreasing rapidly over time in BC. These results provide further evidence that integrated comprehensive free programs that facilitate testing, and deliver treatment and care to this population can be effective in markedly decreasing AIDS-related morbidity and mortality, thus suggesting that controlling and eventually ending AIDS is possible. Funding The British Columbia Ministry of Health, the US National Institutes of Health, the US National Institute on Drug Abuse, the Canadian Institutes of Health Research, and the Michael Institute for

  10. Rituximab maintenance therapy for patients with diffuse large B-cell lymphoma: A meta-analysis

    PubMed Central

    Li, Juan

    2017-01-01

    Purpose The addition of rituximab to standard chemotherapy has significantly improved survival in patients with lymphoma. Recently, maintenance therapy with rituximab has been shown to prevent relapse and provide survival benefits for patients with follicular or mantle cell lymphoma. However, the effects of rituximab in patients with diffuse large B-cell lymphoma (DLBCL) remain unclear. Two new studies involving rituximab in the treatment of DLBCL were performed this past year. We performed a meta analysis to evaluate the effects of rituximab maintenance treatment of patients with DLBCL. Methods Several databases (PubMed, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials) databases were reviewed for relevant randomized controlled trials published prior to May, 2016. Two reviewers assessed the quality of the included studies and extracted data independently. The hazard ratios (HRs) for time-to-event data and relative risks (RRs) for the other data were pooled and estimated. Results Totally 5 studies including 1740 patients were eligible for the meta-analysis. Compared to the observation group, patients who received rituximab maintenance therapy had significantly improved event-free survival (EFS) (HR = 0.80, 95% CI: 0.65–0.98) and progression-free survival (PFS) (HR = 0.72, 95% CI: 0.54–0.94). However, there was no statistically significant difference in overall survival (OS) (HR = 0.66, 95% CI: 0.27–1.29). A subgroup analysis suggested that male patients may benefit from rituximab maintenance therapy with a better EFS (HR = 0.53, 95% CI: 0.34–0.82-), while this advantage was not observed in female patients (HR = 0.99, 95% CI: 0.64–1.52). Conclusions Rituximab maintenance may provide survival benefits beyond that afforded by first- and second-line chemotherapy alone, especially in male patients. However, maintenance rituximab treatment may cause more adverse events. It is recommended that both survival benefits and adverse events should

  11. Benefit of Consolidative Radiation Therapy for Primary Bone Diffuse Large B-Cell Lymphoma

    SciTech Connect

    Tao, Randa; Allen, Pamela K.; Rodriguez, Alma; Shihadeh, Ferial; Pinnix, Chelsea C.; Arzu, Isadora; Reed, Valerie K.; Oki, Yasuhiro; Westin, Jason R.; Fayad, Luis E.; Medeiros, L. Jeffrey; Dabaja, Bouthaina

    2015-05-01

    Purpose: Outcomes for patients with diffuse large B-cell lymphoma (DLBCL) differ according to the site of presentation. With effective chemotherapy, the need for consolidative radiation therapy (RT) is controversial. We investigated the influence of primary bone presentation and receipt of consolidative RT on progression-free survival (PFS) and overall survival (OS) in patients with DLBCL. Methods and Materials: We identified 102 patients with primary bone DLBCL treated consecutively from 1988 through 2013 and extracted clinical, pathologic, and treatment characteristics from the medical records. Survival outcomes were calculated by the Kaplan-Meier method, with factors affecting survival determined by log-rank tests. Univariate and multivariate analyses were done with a Cox regression model. Results: The median age was 55 years (range, 16-87 years). The most common site of presentation was in the long bones. Sixty-five patients (63%) received R-CHOP–based chemotherapy, and 74 (72%) received rituximab. RT was given to 67 patients (66%), 47 with stage I to II and 20 with stage III to IV disease. The median RT dose was 44 Gy (range, 24.5-50 Gy). At a median follow-up time of 82 months, the 5-year PFS and OS rates were 80% and 82%, respectively. Receipt of RT was associated with improved 5-year PFS (88% RT vs 63% no RT, P=.0069) and OS (91% vs 68%, P=.0064). On multivariate analysis, the addition of RT significantly improved PFS (hazard ratio [HR] = 0.14, P=.014) with a trend toward an OS benefit (HR=0.30, P=.053). No significant difference in PFS or OS was found between patients treated with 30 to 35 Gy versus ≥36 Gy (P=.71 PFS and P=.31 OS). Conclusion: Patients with primary bone lymphoma treated with standard chemotherapy followed by RT can have excellent outcomes. The use of consolidative RT was associated with significant benefits in both PFS and OS.

  12. Identification of distinct subgroups of EBV-positive post-transplant diffuse large B-cell lymphoma.

    PubMed

    Morscio, Julie; Finalet Ferreiro, Julio; Vander Borght, Sara; Bittoun, Emilie; Gheysens, Olivier; Dierickx, Daan; Verhoef, Gregor; Wlodarska, Iwona; Tousseyn, Thomas

    2017-03-01

    Post-transplantation lymphoproliferative disorder is an aggressive complication of transplantation, most frequently of diffuse large B-cell lymphoma morphology and associated with Epstein-Barr virus (EBV) infection/reactivation. In this study the microenvironment of EBV(+) (n=23) and EBV(-) (n=9) post-transplant non-germinal center B-cell diffuse large B-cell lymphoma was characterized. Of EBV(+) cases somatic hypermutation analysis, gene expression profiling, and extensive phenotyping were performed. Our results demonstrated variable cytotoxic T-cell infiltration and significantly increased CD163(+) M2 macrophage infiltration in EBV(+) compared with EBV(-) post-transplant diffuse large B-cell lymphoma. On the basis of IgM staining and hypermutation analysis, two EBV(+) post-transplant diffuse large B-cell lymphoma subgroups were identified: IgM(+) tumors lacking somatic hypermutations and IgM(-) tumors harboring somatic hypermutations. IgM(-) tumors arose late following transplantation (median interval: 16 months), mainly in kidney recipients. IgM(+) tumors on the other hand arose early (median interval: 3 months, P-value=0.0032), almost exclusively following stem cell transplantation and were associated with worse outcome (median survival 1 month for IgM(+) versus 41 months for IgM(-) tumors, log-rank/Wilcoxon P-value 0.07/0.04). Notably, IgM(+) tumors were characterized by plasma cell features (monotypic kappa/lambda expression, high MUM1 expression, and partial CD138 expression) and a high proliferation index. Consistent with the plasma cell phenotype, unfolded protein response signaling was upregulated. In contrast, IgM(-) EBV(+) post-transplant diffuse large B-cell lymphoma did not express kappa, lambda, IgD, or CD138 and expressed limited MUM1. In these tumors T-cell signaling was enhanced associated with increased T-cell infiltration compared with IgM(+) cases. Overall, our results allow further molecular classification of EBV(+) post-transplant diffuse

  13. Large-scale optimization-based non-negative computational framework for diffusion equations: Parallel implementation and performance studies

    DOE PAGES

    Chang, Justin; Karra, Satish; Nakshatrala, Kalyana B.

    2016-07-26

    It is well-known that the standard Galerkin formulation, which is often the formulation of choice under the finite element method for solving self-adjoint diffusion equations, does not meet maximum principles and the non-negative constraint for anisotropic diffusion equations. Recently, optimization-based methodologies that satisfy maximum principles and the non-negative constraint for steady-state and transient diffusion-type equations have been proposed. To date, these methodologies have been tested only on small-scale academic problems. The purpose of this paper is to systematically study the performance of the non-negative methodology in the context of high performance computing (HPC). PETSc and TAO libraries are, respectively, usedmore » for the parallel environment and optimization solvers. For large-scale problems, it is important for computational scientists to understand the computational performance of current algorithms available in these scientific libraries. The numerical experiments are conducted on the state-of-the-art HPC systems, and a single-core performance model is used to better characterize the efficiency of the solvers. Furthermore, our studies indicate that the proposed non-negative computational framework for diffusion-type equations exhibits excellent strong scaling for real-world large-scale problems.« less

  14. Large-scale optimization-based non-negative computational framework for diffusion equations: Parallel implementation and performance studies

    SciTech Connect

    Chang, Justin; Karra, Satish; Nakshatrala, Kalyana B.

    2016-07-26

    It is well-known that the standard Galerkin formulation, which is often the formulation of choice under the finite element method for solving self-adjoint diffusion equations, does not meet maximum principles and the non-negative constraint for anisotropic diffusion equations. Recently, optimization-based methodologies that satisfy maximum principles and the non-negative constraint for steady-state and transient diffusion-type equations have been proposed. To date, these methodologies have been tested only on small-scale academic problems. The purpose of this paper is to systematically study the performance of the non-negative methodology in the context of high performance computing (HPC). PETSc and TAO libraries are, respectively, used for the parallel environment and optimization solvers. For large-scale problems, it is important for computational scientists to understand the computational performance of current algorithms available in these scientific libraries. The numerical experiments are conducted on the state-of-the-art HPC systems, and a single-core performance model is used to better characterize the efficiency of the solvers. Furthermore, our studies indicate that the proposed non-negative computational framework for diffusion-type equations exhibits excellent strong scaling for real-world large-scale problems.

  15. Uncovering Implicit Assumptions: A Large-Scale Study on Students' Mental Models of Diffusion

    ERIC Educational Resources Information Center

    Stains, Marilyne; Sevian, Hannah

    2015-01-01

    Students' mental models of diffusion in a gas phase solution were studied through the use of the Structure and Motion of Matter (SAMM) survey. This survey permits identification of categories of ways students think about the structure of the gaseous solute and solvent, the origin of motion of gas particles, and trajectories of solute particles in…

  16. Diffuse gamma-ray emission from pulsars in the Large Magellanic Cloud

    NASA Technical Reports Server (NTRS)

    Hartmann, Dieter H.; Brown, Lawrence E.; Schnepf, Neil

    1993-01-01

    We investigate the contribution of pulsars to the diffuse gamma-ray emission from the LMC. The pulsar birth rate in the LMC is a factor of about 10 lower than that of the Galaxy and the distance to pulsars in the LMC is about 5-10 times larger than to Galactic pulsars. The resulting total integrated photon flux from LMC pulsars is thus reduced by a factor of about 100 to 1000. However, the surface brightness is not reduced by the same amount because of the much smaller angular extent of the LMC in comparison to the diffuse glow from the Galactic plane. We show that gamma-ray emission due to pulsars born in the LMC could produce gamma-ray fluxes that are larger than the inverse Compton component from relativistic cosmic-ray electrons and a significant fraction of the extragalactic isotropic background or the diffuse Galactic background in that direction. The diffuse pulsar glow above 100 MeV should therefore be included in models of high-energy emission from the LMC. For a gamma-ray beaming fraction of order unity the detected emissions from the LMC constrain the pulsar birth rate to less than one per 50 yr. This limit is about one order of magnitude above the supernova rate inferred from the historic record or from the star-formation rate.

  17. Diffusion and Large-Scale Adoption of Computer-Supported Training Simulations in the Military Domain

    DTIC Science & Technology

    2013-09-01

    on diffusion of innovations theory originated in 19th Century European studies of cultural change. This review lists David Emile Durkheim (1858–1917...RESEARCH QUESTIONS ................................19 D. SCOPE .............................................20 E . THESIS CONTRIBUTIONS...44 D. TECHNOLOGY ADOPTION FRAMEWORKS ....................46 E . SERVICE AND GENERAL POPULATION DATA SETS ..........49 1. Service

  18. Parameterization of large-scale turbulent diffusion in the presence of both well-mixed and weakly mixed patchy layers

    NASA Astrophysics Data System (ADS)

    Osman, M. K.; Hocking, W. K.; Tarasick, D. W.

    2016-06-01

    general degrees of mixing. We show that it is the largest, most vigorous and less common turbulent layers that make the major contribution to global diffusion. Finally, we make estimates of global-scale diffusion coefficients in the lower stratosphere and upper troposphere. For the lower stratosphere, κeff ≈ 2x10-2 m2 s-1, assuming no other processes contribute to large-scale diffusion.

  19. Diffuse large B-cell lymphoma arising primarily at the stoma after bladder reconstruction using ileal conduit.

    PubMed

    Muta, Tsuyoshi; Nakaike, Takashi; Fujisaki, Tomoaki; Shiraishi, Takeshi; Ohshima, Koichi

    2012-01-01

    A 76-year-old man suffered from swelling stoma for several weeks. A biopsy sample revealed the diffuse infiltration of large lymphoid cells which were positive for CD20, bcl-6, and MUM1. The patient was diagnosed with diffuse large B-cell lymphoma, with a non-germinal center B-cell pattern. A whole-body PET-CT scan revealed that the lymphoma was restricted to the stomal site. Bladder reconstruction was undertaken using the ileal conduit: this is the first reported case of lymphoma that developed primarily at the stoma. During the long-term maintenance after bladder reconstruction, clinicians should consider the possibility of lymphoma at the stomal site.

  20. Fatal tracheal aspergillosis during rituximab combined chemotherapy for diffuse large B-cell lymphoma that developed after lung transplantation.

    PubMed

    Kawamoto, K; Shibasaki, Y; Sato, S; Nemoto, H; Takizawa, J; Narita, M; Tsuchida, M; Sone, H; Masuko, M

    2015-12-01

    Invasive tracheal aspergillosis (ITA) is an infection that is unique to patients who have undergone lung transplantation (LT). Although the activity of this disease often appears on imaging, we encountered a case of ITA that became exacerbated, despite few computed tomography (CT) findings, during rituximab combined chemotherapy for diffuse large B-cell lymphoma. ITA developed during immunosuppressive therapy after LT. Because CT findings may show false-negative results, bronchoscopy is recommended for such cases.

  1. Large-Eddy/Reynolds-Averaged Navier-Stokes Simulation of Shock-Train Development in a Coil-Laser Diffuser

    DTIC Science & Technology

    2014-09-06

    train formation and reactant mixing in a model Chemical Oxygen Iodine Laser (COIL) unit. The configuration consists of a converging-diverging nozzle, a...appear to influence the mixing process in the lasing cavity significantly. 15. SUBJECT TERMS Large-eddy simulation, chemical oxygen iodine lasers...model Chemical Oxygen Iodine Laser (COIL) unit. The configuration consists of a converging-diverging nozzle, a lasing cavity, and a diffuser. The

  2. CGCI Investigators Reveal Comprehensive Landscape of Diffuse Large B-Cell Lymphoma (DLBCL) Genomes | Office of Cancer Genomics

    Cancer.gov

    Researchers from British Columbia Cancer Agency used whole genome sequencing to analyze 40 DLBCL cases and 13 cell lines in order to fill in the gaps of the complex landscape of DLBCL genomes. Their analysis, “Mutational and structural analysis of diffuse large B-cell lymphoma using whole genome sequencing,” was published online in Blood on May 22. The authors are Ryan Morin, Marco Marra, and colleagues.  

  3. Evolution of frontline treatment of diffuse large B-cell lymphoma: a brief review and recent update

    PubMed Central

    Hong, Jung Yong; Suh, Cheolwon; Kim, Won Seog

    2016-01-01

    Various strategies have been implemented to improve the outcomes of diffuse large B-cell lymphoma (DLBCL). In recent years, remarkable advances have been achieved, based on the discovery of cell-of-origin in DLBCL and on more effective targeted agents. This commentary will summarize recent updates on the evolution of frontline therapies for DLBCL, focusing on the upcoming promising frontline chemotherapy platforms and on activated B-cell subtype DLBCL and double-hit DLBCL. PMID:27606052

  4. A Unique "Composite" PTLD with Diffuse Large B-Cell and T/Anaplastic Large Cell Lymphoma Components Occurring 17 Years after Transplant.

    PubMed

    La Fortune, Kristin; Zhang, Dahua; Raca, Gordana; Ranheim, Erik A

    2013-01-01

    Posttransplant lymphoproliferative disorder (PTLD) comprises a spectrum ranging from polyclonal hyperplasia to aggressive monoclonal lymphomas. The majority of PTLDs are of B-cell origin while T-cell PTLDs and Hodgkin lymphoma-like PTLDs are uncommon. Here, we report a unique case of a 56-year-old man in whom a lymphoma with two distinct components developed as a duodenal mass seventeen years following a combined kidney-pancreas transplant. This PTLD, which has features not previously reported in the literature, consisted of one component of CD20 positive and EBV negative monomorphic diffuse large B-cell lymphoma. The other component showed anaplastic morphology, expressed some but not all T-cell markers, failed to express most B-cell markers except for PAX5, and was diffusely EBV positive. Possible etiologies for this peculiar constellation of findings are discussed and the literature reviewed for "composite-like" lymphomas late in the posttransplant setting.

  5. Adsorption and diffusion of Ru adatoms on Ru(0001)-supported graphene: Large-scale first-principles calculations

    SciTech Connect

    Han, Yong; Evans, James W.

    2015-10-28

    Large-scale first-principles density functional theory calculations are performed to investigate the adsorption and diffusion of Ru adatoms on monolayer graphene (G) supported on Ru(0001). The G sheet exhibits a periodic moiré-cell superstructure due to lattice mismatch. Within a moiré cell, there are three distinct regions: fcc, hcp, and mound, in which the C{sub 6}-ring center is above a fcc site, a hcp site, and a surface Ru atom of Ru(0001), respectively. The adsorption energy of a Ru adatom is evaluated at specific sites in these distinct regions. We find the strongest binding at an adsorption site above a C atom in the fcc region, next strongest in the hcp region, then the fcc-hcp boundary (ridge) between these regions, and the weakest binding in the mound region. Behavior is similar to that observed from small-unit-cell calculations of Habenicht et al. [Top. Catal. 57, 69 (2014)], which differ from previous large-scale calculations. We determine the minimum-energy path for local diffusion near the center of the fcc region and obtain a local diffusion barrier of ∼0.48 eV. We also estimate a significantly lower local diffusion barrier in the ridge region. These barriers and information on the adsorption energy variation facilitate development of a realistic model for the global potential energy surface for Ru adatoms. This in turn enables simulation studies elucidating diffusion-mediated directed-assembly of Ru nanoclusters during deposition of Ru on G/Ru(0001)

  6. Adsorption and diffusion of Ru adatoms on Ru(0001)-supported graphene: Large-scale first-principles calculations

    DOE PAGES

    Han, Yong; Evans, James W.

    2015-10-27

    Large-scale first-principles density functional theory calculations are performed to investigate the adsorption and diffusion of Ru adatoms on monolayer graphene (G) supported on Ru(0001). The G sheet exhibits a periodic moiré-cell superstructure due to lattice mismatch. Within a moiré cell, there are three distinct regions: fcc, hcp, and mound, in which the C6-ring center is above a fcc site, a hcp site, and a surface Ru atom of Ru(0001), respectively. The adsorption energy of a Ru adatom is evaluated at specific sites in these distinct regions. We find the strongest binding at an adsorption site above a C atom inmore » the fcc region, next strongest in the hcp region, then the fcc-hcp boundary (ridge) between these regions, and the weakest binding in the mound region. Behavior is similar to that observed from small-unit-cell calculations of Habenicht et al. [Top. Catal. 57, 69 (2014)], which differ from previous large-scale calculations. We determine the minimum-energy path for local diffusion near the center of the fcc region and obtain a local diffusion barrier of ~0.48 eV. We also estimate a significantly lower local diffusion barrier in the ridge region. These barriers and information on the adsorption energy variation facilitate development of a realistic model for the global potential energy surface for Ru adatoms. Furthermore, this in turn enables simulation studies elucidating diffusion-mediated directed-assembly of Ru nanoclusters during deposition of Ru on G/Ru(0001).« less

  7. Adsorption and diffusion of Ru adatoms on Ru(0001)-supported graphene: Large-scale first-principles calculations

    SciTech Connect

    Han, Yong; Evans, James W.

    2015-10-27

    Large-scale first-principles density functional theory calculations are performed to investigate the adsorption and diffusion of Ru adatoms on monolayer graphene (G) supported on Ru(0001). The G sheet exhibits a periodic moiré-cell superstructure due to lattice mismatch. Within a moiré cell, there are three distinct regions: fcc, hcp, and mound, in which the C6-ring center is above a fcc site, a hcp site, and a surface Ru atom of Ru(0001), respectively. The adsorption energy of a Ru adatom is evaluated at specific sites in these distinct regions. We find the strongest binding at an adsorption site above a C atom in the fcc region, next strongest in the hcp region, then the fcc-hcp boundary (ridge) between these regions, and the weakest binding in the mound region. Behavior is similar to that observed from small-unit-cell calculations of Habenicht et al. [Top. Catal. 57, 69 (2014)], which differ from previous large-scale calculations. We determine the minimum-energy path for local diffusion near the center of the fcc region and obtain a local diffusion barrier of ~0.48 eV. We also estimate a significantly lower local diffusion barrier in the ridge region. These barriers and information on the adsorption energy variation facilitate development of a realistic model for the global potential energy surface for Ru adatoms. Furthermore, this in turn enables simulation studies elucidating diffusion-mediated directed-assembly of Ru nanoclusters during deposition of Ru on G/Ru(0001).

  8. Occurrence of anaplastic large cell lymphoma following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma.

    PubMed

    Ishida, Mitsuaki; Hodohara, Keiko; Yoshida, Keiko; Kagotani, Akiko; Iwai, Muneo; Yoshii, Miyuki; Okuno, Hiroko; Horinouchi, Akiko; Nakanishi, Ryota; Harada, Ayumi; Yoshida, Takashi; Okabe, Hidetoshi

    2013-01-01

    IgG4-related sclerosing disease is an established disease entity with characteristic clinicopathological features. Recently, the association between IgG4-related sclerosing disease and the risk of malignancies has been suggested. IgG4-related autoimmune pancreatitis with pancreatic cancer has been reported. Further, a few cases of extraocular malignant lymphoma in patients with IgG4-related sclerosing disease have also been documented. Herein, we describe the first documented case of anaplastic large cell lymphoma (ALCL) following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma (DLBCL). A 61-year-old Japanese male, with a past history of DLBCL, was detected with swelling of the pancreas and tumorous lesions in the gallbladder. Histopathological study of the resected gallbladder specimen revealed diffuse lymphoplasmacytic infiltration with fibrosclerosis in the entire gallbladder wall. Eosinophilic infiltration and obliterative phlebitis were also noted. Immunohistochemically, many IgG4-positive plasma cells had infiltrated into the lesion, and the ratio of IgG4/IgG-positive plasma cells was 71.6%. Accordingly, a diagnosis of IgG4-related cholecystitis was made. Seven months later, he presented with a painful tumor in his left parotid gland. Histopathological study demonstrated diffuse or cohesive sheet-like proliferation of large-sized lymphoid cells with rich slightly eosinophilic cytoplasm and irregular-shaped large nuclei. These lymphoid cells were positive for CD30, CD4, and cytotoxic markers, but negative for CD3 and ALK. Therefore, a diagnosis of ALK-negative ALCL was made. It has been suggested that the incidence of malignant lymphoma may be high in patients with IgG4-related sclerosing disease, therefore, intense medical follow-up is important in patients with this disorder.

  9. Digital holographic interferometry with CO2 lasers and diffuse illumination applied to large space reflector metrology [Invited].

    PubMed

    Georges, Marc P; Vandenrijt, Jean-François; Thizy, Cédric; Stockman, Yvan; Queeckers, Patrick; Dubois, Frank; Doyle, Dominic

    2013-01-01

    Digital holographic interferometry in the long-wave infrared domain has been developed by combining a CO(2) laser and a microbolometer array. The long wavelength allows large deformation measurements, which are of interest in the case of large space reflectors undergoing thermal changes when in orbit. We review holography at such wavelengths and present some specific aspects related to this spectral range on our measurements. For the design of our digital holographic interferometer, we studied the possibility of illuminating specular objects by a reflective diffuser. We discuss the development of the interferometer and the results obtained on a representative space reflector, first in the laboratory and then during vacuum cryogenic test.

  10. Parallel STEPS: Large Scale Stochastic Spatial Reaction-Diffusion Simulation with High Performance Computers.

    PubMed

    Chen, Weiliang; De Schutter, Erik

    2017-01-01

    Stochastic, spatial reaction-diffusion simulations have been widely used in systems biology and computational neuroscience. However, the increasing scale and complexity of models and morphologies have exceeded the capacity of any serial implementation. This led to the development of parallel solutions that benefit from the boost in performance of modern supercomputers. In this paper, we describe an MPI-based, parallel operator-splitting implementation for stochastic spatial reaction-diffusion simulations with irregular tetrahedral meshes. The performance of our implementation is first examined and analyzed with simulations of a simple model. We then demonstrate its application to real-world research by simulating the reaction-diffusion components of a published calcium burst model in both Purkinje neuron sub-branch and full dendrite morphologies. Simulation results indicate that our implementation is capable of achieving super-linear speedup for balanced loading simulations with reasonable molecule density and mesh quality. In the best scenario, a parallel simulation with 2,000 processes runs more than 3,600 times faster than its serial SSA counterpart, and achieves more than 20-fold speedup relative to parallel simulation with 100 processes. In a more realistic scenario with dynamic calcium influx and data recording, the parallel simulation with 1,000 processes and no load balancing is still 500 times faster than the conventional serial SSA simulation.

  11. Parallel STEPS: Large Scale Stochastic Spatial Reaction-Diffusion Simulation with High Performance Computers

    PubMed Central

    Chen, Weiliang; De Schutter, Erik

    2017-01-01

    Stochastic, spatial reaction-diffusion simulations have been widely used in systems biology and computational neuroscience. However, the increasing scale and complexity of models and morphologies have exceeded the capacity of any serial implementation. This led to the development of parallel solutions that benefit from the boost in performance of modern supercomputers. In this paper, we describe an MPI-based, parallel operator-splitting implementation for stochastic spatial reaction-diffusion simulations with irregular tetrahedral meshes. The performance of our implementation is first examined and analyzed with simulations of a simple model. We then demonstrate its application to real-world research by simulating the reaction-diffusion components of a published calcium burst model in both Purkinje neuron sub-branch and full dendrite morphologies. Simulation results indicate that our implementation is capable of achieving super-linear speedup for balanced loading simulations with reasonable molecule density and mesh quality. In the best scenario, a parallel simulation with 2,000 processes runs more than 3,600 times faster than its serial SSA counterpart, and achieves more than 20-fold speedup relative to parallel simulation with 100 processes. In a more realistic scenario with dynamic calcium influx and data recording, the parallel simulation with 1,000 processes and no load balancing is still 500 times faster than the conventional serial SSA simulation. PMID:28239346

  12. A method to analyze the diffuse gamma-ray emission with the Fermi Large Area Telescope

    SciTech Connect

    Ackermann, Markus; Johannesson, Gueolaugur; Digel, Seth; Moskalenko, Igor V.; Reimer, Olaf; Porter, Troy; Strong, Andrew

    2008-12-24

    The Fermi Gamma-Ray Space Telescope with its main instrument the LAT is the most sensitive {gamma}-ray telescope in the energy region between 30 MeV and 100 GeV. One of the prime scientific goals of this mission is the measurement and interpretation of the diffuse Galactic and extragalactic {gamma}-ray emission. While not limited by photon statistics, this analysis presents several challenges: Instrumental response functions, residual background from cosmic rays as well as resolved and unresolved foreground {gamma}-ray sources have to be taken carefully into account in the interpretation of the data. Detailed modeling of the diffuse {gamma}-ray emission is being performed and will form the basis of the investigations. We present the analysis approach to be applied to the Fermi LAT data, namely the modeling of the diffuse emission components and the background contributions, followed by an all-sky maximum-likelihood fitting procedure. We also report on the performance of this method evaluated in tests on simulated Fermi LAT and real EGRET data.

  13. Older female caregivers and HIV/AIDS-related secondary stigma in rural South Africa.

    PubMed

    Ogunmefun, Catherine; Gilbert, Leah; Schatz, Enid

    2011-03-01

    South Africa's HIV/AIDS epidemic poses a major public health threat with multi-faceted harmful impacts and 'socially complex' outcomes. While some outcomes relate to structural issues, others stem from society's attitudinal milieu. Due to negative attitudes toward People Living with HIV/AIDS, stigmatisation mars their own experience and often extends to those close to them, in particular their caregivers. Many of the caregivers in South Africa are older women; thus, older women are the focus of this paper, which aims to examine HIV/AIDS-related stigma from their perspective. This paper explores secondary stigma as a socio-cultural impact of HIV/AIDS through repeated semistructured interviews with 60 women aged 50-75 in the MRC/Wits Rural Public Health and Health Transitions Unit research site (Agincourt), many of whom had cared for a family member with HIV/AIDS. Respondents' narratives reveal that many older persons attribute high rates of death in their community to young persons' lack of respect for societal norms and traditions. The findings illustrate the forms and expressions of HIV/AIDS-related secondary stigma and their impacts on older female caregivers. The types of secondary stigma experienced by the respondents include physical stigma in the form of isolation and separation from family members; social stigma in the form of voyeurism and social isolation; and verbal stigma in the form of being gossiped about, finger-pointing and jeering at them. Despite mixed reports about community responses toward infected and affected people, HIV/AIDS-related stigma remains a cause for concern, as evidenced by the reports of older women in this study.

  14. Lab on a chip Canada--rapid diffusion over large length scales.

    PubMed

    Juncker, David; Wheeler, Aaron R; Sinton, David

    2013-07-07

    The roots of lab on a chip in Canada are deep, comprising of some of the earliest contributions and first demonstrations of the potential of microfluidic chips. In an editorial leading off this special issue, Jed Harrison of University of Alberta reflects on these early days and Canada's role in the field's development (DOI: 10.1039/c3lc50522g). Over the last decade, microfluidics and lab-on-a-chip research efforts grew exponentially - rapidly diffusing across the vast Canadian length scales.

  15. Large-amplitude chirped coherent phonons in tellurium mediated by ultrafast photoexcited carrier diffusion

    NASA Astrophysics Data System (ADS)

    Kamaraju, N.; Kumar, Sunil; Anija, M.; Sood, A. K.

    2010-11-01

    We report femtosecond time-resolved reflectivity measurements of coherent phonons in tellurium performed over a wide range of temperatures (3-296 K) and pump-laser intensities. A totally symmetric A1 coherent phonon at 3.6 THz responsible for the oscillations in the reflectivity data is observed to be strongly positively chirped (i.e., phonon time period decreases at longer pump-probe delay times) with increasing photoexcited carrier density, more so at lower temperatures. We show that the temperature dependence of the coherent phonon frequency is anomalous (i.e, increasing with increasing temperature) at high photoexcited carrier density due to electron-phonon interaction. At the highest photoexcited carrier density of ˜1.4×1021cm-3 and the sample temperature of 3 K, the lattice displacement of the coherent phonon mode is estimated to be as high as ˜0.24Å . Numerical simulations based on coupled effects of optical absorption and carrier diffusion reveal that the diffusion of carriers dominates the nonoscillatory electronic part of the time-resolved reflectivity. Finally, using the pump-probe experiments at low carrier density of 6×1018cm-3 , we separate the phonon anharmonicity to obtain the electron-phonon coupling contribution to the phonon frequency and linewidth.

  16. The formation of thermohaline staircases for large salt concentration differences in double diffusive convection

    NASA Astrophysics Data System (ADS)

    Yang, Yantao; Verzicco, Roberto; Lohse, Detlef

    2016-11-01

    In the upper layers of the tropical and subtropical ocean, step-like mean profiles for both temperature and salinity are often observed, a phenomenon referred to as thermohaline staircase. It consists of alternatively stacked mixing layers, and finger layers with sharp gradients in both mean temperature and salinity. It is believed that thermohaline staircases are caused by double diffusive convection (DDC), i.e. the convection flow with fluid density affected by two different scalars. Here we conducted direct numerical simulations of DDC bounded by two parallel plates and aimed to realise the multi-layer state similar to the oceanic thermohaline staircase. We applied an unstable salinity difference and a stable temperature difference across the two plates. We gradually increased the salinity Rayleigh number RaS , i.e. the strength of salinity difference, and fixed the relative strength of temperature difference. When RaS is high enough the flow undergoes a transition from a single finger layer to a triple layer state, where one mixing layer emerges between two finger layers. Such triple layer state is stable up to the turbulent diffusive time scale. The finger-layer height is larger for higher RaS . The dependences of the scalar fluxes on RaS were also investigated. Supported by Dutch FOM Foundation and NWO rpogramme MCEC; Computing resources from SURFSara and PRACE project 2015133124.

  17. Fungal infections in patients with AIDS and AIDS-related complex.

    PubMed

    Holmberg, K; Meyer, R D

    1986-01-01

    Persons with AIDS are predisposed to a variety of previously rare bacterial and fungal infections. Improvement in the quality and duration of survival of AIDS patients depends on the efficacy of treatment for these infections. Between 58-81% of AIDS patients contract fungal infections at some time, and 10-20% of AIDS patients die as a direct consequence of such infections. Oral candidiasis, commonly known as thrush, is the most common fungal infection among AIDS and AIDS Related Complex patients, occurring in 80-90% of cases. In a recent U.S. study, 59% of persons with oral candidiasis who were at high risk of contracting AIDS went on to develop Kaposi's sarcoma and other life- threatening infections. The most common life-threatening fungal infection experienced by AIDS patients is cryptococcosis, a disease occurring among 6% of American AIDS patients and having a mortality rate of 17% during initial infections and 75-100% on relapse. Other opportunistic infections associated with AIDS and AIDS Related Complex are bronchial candidiasis, invasive aspergillosis, disseminated histoplasmosis, and disseminated coccidioidomycosis. All are treatable but eradication i s difficult and relapse common.

  18. Salvage Therapy for Refractory Aids-Related Primary Central Nervous System Lymphoma

    PubMed Central

    Ferro, Hugo; Parino, Eduardo

    2012-01-01

    A 27-year-old male patient presented with speech disorders and multiple brain masses on MRI evaluation. He tested positive for HIV. A sterotactic biopsy diagnosed primary central nervous system lymphoma (diffuse large B-cell lymphoma). After two cycles of high-dose metotrexate (HD-MTX-)-based chemotherapy, the tumor progressed. He underwent whole brain radiotherapy achieving complete response. Six cycles of consolidating immunochemotherapy with rituximab-temozolomide were administered after radiation. Forty-three months after remission, he has not recurred and his neurological status is optimal. Younger HIV patients with refractory PCNSL and preserved immune function can face salvage therapy successfully achieving long term remissions with no remarkable neurotoxicity. PMID:23029628

  19. Salvage therapy for refractory AIDS-related primary central nervous system lymphoma.

    PubMed

    Ferro, Hugo; Parino, Eduardo

    2012-01-01

    A 27-year-old male patient presented with speech disorders and multiple brain masses on MRI evaluation. He tested positive for HIV. A sterotactic biopsy diagnosed primary central nervous system lymphoma (diffuse large B-cell lymphoma). After two cycles of high-dose metotrexate (HD-MTX-)-based chemotherapy, the tumor progressed. He underwent whole brain radiotherapy achieving complete response. Six cycles of consolidating immunochemotherapy with rituximab-temozolomide were administered after radiation. Forty-three months after remission, he has not recurred and his neurological status is optimal. Younger HIV patients with refractory PCNSL and preserved immune function can face salvage therapy successfully achieving long term remissions with no remarkable neurotoxicity.

  20. Morphologic studies of lymphocyte nuclei in follicular and diffuse mixed small- and large-cell (lymphocytic-histiocytic) lymphoma.

    PubMed

    Dardick, I; Caldwell, D R; Moher, D; Jabi, M

    1988-08-01

    Twelve examples of mixed small- and large-cell lymphoma (eight follicular, one follicular and diffuse, and three diffuse) were investigated morphometrically using plastic-embedded tissue in order to study nuclear characteristics of lymphocyte populations in this form of non-Hodgkin's lymphoma (NHL) and to test morphologic bases for current NHL classification systems. This study illustrates that there are many inaccuracies, illusions, and misconceptions in the morphologic criteria currently used to classify mixed small- and large-cell lymphoma. A principal finding was that lymphocyte nuclear profiles in mixed-cell lymphomas tend to be smaller in size (P less than .005) and more irregular in shape (P = .0001) than the morphologically similar counterparts in germinal centers of lymph nodes with reactive hyperplasia. Intercase comparison of mixed small- and large-cell lymphomas revealed a considerable range of mean nuclear area values, some of which were within the size range of normal, small lymphocytes. At the magnifications used for morphometric assessment, a high proportion of lymphocyte nuclear profiles had shallow invaginations, but only a limited number of profiles (4% to 14%) had deep (cleaved) indentations. Contrary to current definitions for this subtype of NHL, lymphocytes with "small" nuclei had the same proportion of the nuclear diameter occupied by nuclear invaginations as lymphocytes with "large" nuclei and, in fact, mean nuclear invagination depth was shallower in "small" nuclei than in "large" nuclei. Furthermore, regardless of whether it is nuclear area or shape that is evaluated, lymphocytes in mixed-cell lymphoma do not separate into two populations of small-cleaved and large noncleaved cells. Morphometry reveals that only four of the 12 examples of mixed small- and large-cell lymphoma had a proportion of the lymphocytes in the size range of fully transformed germinal center lymphocytes that exceeded 25%, and none of the cases approached 50% even

  1. Diffuse large B-cell lymphoma of the parotid gland: Cytological, histopathological, and immunohistochemical features: A rare case report

    PubMed Central

    Andola, Sainath K; Masgal, Meenakshi M; Reddy, Rajeev M

    2016-01-01

    Primary malignant lymphomas of the salivary glands are rare, accounting for 2-5% of salivary gland tumors and 5% of extranodal lymphomas, frequently seen in the parotid gland. There are single case reports mentioned in the literature. Clinical presentation is not characteristic and the disease is often overlooked with delay in diagnosis and treatment. We are reporting a case of bilateral parotid gland lymphoma in a 55-year-old male, presented with bilateral enlarged parotids. Magnetic resonance imaging (MRI) showed bilateral enlarged parotid glands with multiple well-defined intraparotid lesions. Fine Needle Aspiration Cytology (FNAC) of both showed mixed population of lymphoid cells with large monocytoid cells with scant cytoplasm, anisonucleosis with prominent nucleoli, and numerous mitoses suggestive of non-Hodgkin's lymphoma (NHL). Histopathology showed sheets of large lymphoma cells destructing the salivary acini and infiltrating the periparotid fat. Immunohistochemistry (IHC) showed diffuse CD20 positivity, B-cell lymphoma 6 protein (Bcl-6) was focally positive and negative for cluster of differentiation (CD) 3, CD5, CD10, and Multiple myeloma oncogene-1 (MUM1) which led to the diagnosis of NHL-Diffuse large B cell type. PMID:28028340

  2. Extra-nodal Diffuse Large B-cell Lymphoma (Germinal Center Type) Manifesting as Non-healing Extraction Socket

    PubMed Central

    Basavarajappa, Manjunath Anekonda; Pathan, Sana; Raheem, Ahmed Mujib Bangalore; Godavarthy, Divyasri

    2016-01-01

    Lymphomas occurring in the oral cavity are rare. They account only for about 2% of extra-nodal sites. Most of the lymphomas occur in the lymph nodes and in the oral cavity, the most commonly affected region is the Waldeyer’s ring. Its occurrence in the mandibular gingiva is rare. Here, we describe a case of Diffuse Large B-cell Lymphoma manifested as a non-healing extraction socket in the mandibular right posterior region in a 62-year-old male patient. PMID:27656575

  3. Primary central nervous system B cell lymphoma with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma

    PubMed Central

    Jiang, Liuyan; Li, Zhimin; Finn, Laura E; Personnet, David A; Edenfield, Brandy; Foran, James M; Jaeckle, Kurt A; Reimer, Ronald; Menke, David M; Ketterling, Rhett P; Tun, Han W

    2012-01-01

    B cell lymphoma with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma (DLBCL/BL) is a new lymphoma entity which is recognized in the current World Health Organization (WHO) classification (2008). We report a case of a primary central nervous system lymphoma (PCNSL) with findings consistent with DLBCL/BL. It is characterized by a very aggressive clinical course, and a widespread multifocal involvement of the CNS. Our case shows that a DLBCL/BL can manifest in the CNS alone without any systemic involvement. PMID:22295149

  4. New strategies in diffuse large B-cell lymphoma: translating findings from gene expression analyses into clinical practice.

    PubMed

    Friedberg, Jonathan W

    2011-10-01

    Gene expression profiling has had a major impact on our understanding of the biology and heterogeneity of diffuse large B-cell lymphoma (DLBCL). Using this technology, investigators can identify biologic subgroups of DLBCL that provide unique targets for rational therapeutic intervention. This review summarizes these potential targets and updates the progress of clinical development of exciting novel agents for the treatment of DLBCL. Results of ongoing studies suggest that in the near future, we will be able to use gene expression profiling, or an accurate surrogate, to define the best therapeutic approach for individual patients with DLBCL.

  5. Strategies for Diagnosing and Alleviating Artifactual Attenuation Associated with Large Gradient Pulses in PGSE NMR Diffusion Measurements

    NASA Astrophysics Data System (ADS)

    Price, William S.; Hayamizu, Kikuko; Ide, Hiroyuki; Arata, Yoji

    1999-08-01

    The generation of phase-based artifacts resulting from mismatch in the effective areas (i.e., the time integrals) of sequential gradient pulses is discussed in the context of large gradient pulsed-gradient spin-echo (PGSE) NMR diffusion measurements. Such effects result in artifactual attenuation and distortion in the spectra which, in the first instance, are similar to (and commonly mistaken for) the effects of eddy currents. Small degrees of mismatch cause "unphysical" concave downward curvature in PGSE attenuation plots of freely diffusing species. However, larger mismatches can result in artifactual diffraction peaks in the plots which could easily be confused for true restricted diffusion effects. Although "rectangular" gradient pulses are preferable from a theoretical viewpoint, we found that shaped gradient (e.g., half-sine) pulses, which due to their slower rise and fall times were more tractable for the current amplifier, were more sequentially reproducible. As well as generating fewer phase-based artifacts such shaped pulses also decrease the likelihood of vibration problems.

  6. Tracking timescales of short-term precursors to large basaltic fissure eruptions through Fe-Mg diffusion in olivine

    NASA Astrophysics Data System (ADS)

    Hartley, Margaret E.; Morgan, Daniel J.; Maclennan, John; Edmonds, Marie; Thordarson, Thor

    2016-04-01

    Petrological constraints on the timescales of pre-eruptive crystal storage and magma degassing provide an important framework for the interpretation of seismic, geodetic and gas monitoring data in volcanically active regions. We have used Fe-Mg diffusion chronometry in 86 olivine macrocrysts from the AD 1783-1784 Laki eruption on Iceland's Eastern Volcanic Zone to characterise timescales of crystal storage and transport in the lead-up to this eruption. The majority of these olivines have core compositions of Fo < 76, and rim compositions in the range Fo69-Fo74 that are close to equilibrium with the Laki melt. Diffusion modelling using the greyscale intensity of backscattered electron images as a proxy for olivine composition reveals that the most probable Fe-Mg diffusion timescale for Laki olivines is 7.8 days, which reflects the characteristic olivine residence time in the carrier melt prior to eruption. A small population of Fo > 81 olivines record Fe-Mg diffusion timescales of ∼124 days; these crystals are likely to have formed in mid-crustal magma chambers, been transferred to storage at shallower levels and then entrained into the Laki melt prior to eruption. Typical Fe-Mg diffusion timescales of 6-10 days are shorter than the average time interval between discrete episodes of the Laki eruption, indicating variable or pulsed disaggregation of stored crystals into the carrier liquid prior to the onset of each episode. The diffusion timescales coincide with historical accounts of strong and frequent earthquakes in southeast Iceland, which we interpret as being associated with mush disaggregation related to melt withdrawal and the initiation of dyke propagation from a crustal magma reservoir at ∼6 ± 3 km depth to the surface. We calculate pre-eruptive CO2 fluxes of 2-6 Mt d-1, assuming a pre-eruptive CO2 outgassing budget of 189.6 Mt for the Laki eruption and a constant rate of CO2 release in the 6-10 days preceding each eruptive episode. Our dataset

  7. Fragmented Molecular Orbital with Diffusion Monte Carlo for large molecular systems

    NASA Astrophysics Data System (ADS)

    Benali, Anouar; Pruitt, Spencer R.; Fedorov, Dmitri G.

    Performing accurate quantum mechanics (QM) calculations on larger and larger systems, while maintaining a high level of accuracy is an ongoing effort in many ab initio fields. Many different attempts have been made to develop highly scalable and accurate methods. The fragment molecular orbital (FMO) method is an ab initio method capable of taking advantage of modern supercomputers, such as the Blue Gene Q system Mira at the Argonne National Laboratory Leadership Computing Facility (ALCF). FMO is based on dividing molecules into fragments and performing ab initio calculations on fragments, their dimers and, optionally, trimers. This decomposition makes it possible to perform QM calculations of real size biological molecules. In contrast to many other fragment-based methods, the effect of the environment is rigorously accounted for by computing the electrostatic potential (ESP) due to remaining fragments that are not explicitly included in a given monomer, dimer, or trimer calculation. The use of highly accurate levels of theory, such as Diffusion Monte Carlo (DMC-QMC), in conjunction with FMO allows for the goal of highly scalable and accurate all electron calculations demonstrated in this study, on a variety of relevant systems (H2O)[3-6] and protein using GAMESS and QMCPACK.

  8. Orphanhood by AIDS-Related Causes and Child Mental Health: A Developmental Psychopathology Approach

    PubMed Central

    Sharp, Carla; Jardin, Charles; Marais, Lochner; Boivin, Michael

    2016-01-01

    While the number of new HIV infections has declined, the number of orphans as a result of AIDS-related deaths continues to increase. The aim of this paper was to systematically review empirical research on the mental health of children affected by HIV/AIDS in the developing world, specifically with an eye on developing a theoretical framework to guide intervention and research. Articles for review were gathered by following the Preferred Reporting Items for Systemic Reviews and Meta Analyses (PRISMA standards), reviewed and then organized and synthesized with a Developmental Psychopathology framework. Results showed that the immediate and longterm effects of AIDS orphanhood are moderated by a number of important risk and protective factors that may serve as strategic targets for intervention. Research and clinical implications are discussed. PMID:27668289

  9. Understanding and Addressing AIDS-Related Stigma: From Anthropological Theory to Clinical Practice in Haiti

    PubMed Central

    Castro, Arachu; Farmer, Paul

    2005-01-01

    For the past several years, diverse and often confused concepts of stigma have been invoked in discussions on AIDS. Many have argued compellingly that AIDS-related stigma acts as a barrier to voluntary counseling and testing. Less compelling are observations regarding the source of stigma or its role in decreasing interest in HIV care. We reviewed these claims as well as literature from anthropology, sociology, and public health. Preliminary data from research in rural Haiti suggest that the introduction of quality HIV care can lead to a rapid reduction in stigma, with resulting increased uptake of testing. Rather than stigma, logistic and economic barriers determine who will access such services. Implications for scale-up of integrated AIDS prevention and care are explored. PMID:15623859

  10. Effects of Smoking on Non-AIDS-Related Morbidity in HIV-Infected Patients

    PubMed Central

    Shirley, Daniel K.; Kaner, Robert J.; Glesby, Marshall J.

    2013-01-01

    Tobacco smoking has many adverse health consequences. Patients with human immunodeficiency virus (HIV) infection smoke at very high rates, and many of the comorbidities associated with smoking in the general population are more prevalent in this population. It is likely that a combination of higher smoking rates along with an altered response to cigarette smoke throughout the body in persons with HIV infection leads to increased rates of the known conditions related to smoking. Several AIDS-defining conditions associated with smoking have been reviewed elsewhere. This review aims to summarize the data on non-AIDS-related health consequences of smoking in the HIV-infected population and explore evidence for the potential compounding effects on chronic systemic inflammation due to HIV infection and smoking. PMID:23572487

  11. N-linked Glycosylation Enrichment for In-depth Cell Surface Proteomics of Diffuse Large B-cell Lymphoma Subtypes*

    PubMed Central

    Deeb, Sally J.; Cox, Juergen; Schmidt-Supprian, Marc; Mann, Matthias

    2014-01-01

    Global analysis of lymphoma genome integrity and transcriptomes tremendously advanced our understanding of their biology. Technological advances in mass spectrometry-based proteomics promise to complete the picture by allowing the global quantification of proteins and their post-translational modifications. Here we use N-glyco FASP, a recently developed mass spectrometric approach using lectin-enrichment, in conjunction with a super-SILAC approach to quantify N-linked glycoproteins in lymphoma cells. From patient-derived diffuse large B-cell lymphoma cell lines, we mapped 2383 glycosites on 1321 protein groups, which were highly enriched for cell membrane proteins. This N-glyco subproteome alone allowed the segregation of the ABC from the GCB subtypes of diffuse large B-cell lymphoma, which before gene expression studies had been considered one disease entity. Encouragingly, many of the glycopeptides driving the segregation belong to proteins previously characterized as segregators in a deep proteome study of these subtypes (S. J. Deeb et al. MCP 2012 PMID 22442255). This conforms to the high correlation that we observed between the expression level of the glycosites and their corresponding proteins. Detailed examination of glycosites and glycoprotein expression levels uncovered, among other interesting findings, enrichment of transcription factor binding motifs, including known NF-kappa-B related ones. Thus, enrichment of a class of post-translationally modified peptides can classify cancer types as well as reveal cancer specific mechanistic changes. PMID:24190977

  12. Terahertz Conductivity within Colloidal CsPbBr3 Perovskite Nanocrystals: Remarkably High Carrier Mobilities and Large Diffusion Lengths.

    PubMed

    Yettapu, Gurivi Reddy; Talukdar, Debnath; Sarkar, Sohini; Swarnkar, Abhishek; Nag, Angshuman; Ghosh, Prasenjit; Mandal, Pankaj

    2016-08-10

    Colloidal CsPbBr3 perovskite nanocrystals (NCs) have emerged as an excellent light emitting material in last one year. Using time domain and time-resolved THz spectroscopy and density functional theory based calculations, we establish 3-fold free carrier recombination mechanism, namely, nonradiative Auger, bimolecular electron-hole recombination, and inefficient trap-assisted recombination in 11 nm sized colloidal CsPbBr3 NCs. Our results confirm a negligible influence of surface defects in trapping charge carriers, which in turn results into desirable intrinsic transport properties, from the perspective of device applications, such as remarkably high carrier mobility (∼4500 cm(2) V(-1) s(-1)), large diffusion length (>9.2 μm), and high luminescence quantum yield (80%). Despite being solution processed and possessing a large surface to volume ratio, this combination of high carrier mobility and diffusion length, along with nearly ideal photoluminescence quantum yield, is unique compared to any other colloidal quantum dot system.

  13. Understanding Internalized HIV/AIDS-Related Stigmas in the Dominican Republic: A Short Report

    PubMed Central

    Hampanda, Karen

    2016-01-01

    HIV/AIDS-related stigmas can become internalized, resulting in declines in physical and mental health. Pathways to internalized HIV-related stigma (IS), characterized by persistently negative, self-abasing thoughts, are not well established among women living with HIV/AIDS (WLWHA) in the Dominican Republic (DR). Identifying factors involved in self-directed shaming and blaming is important, given the high HIV prevalence in the DR’s most vulnerable populations. The present study sheds light on factors involved in negative and self-abasing thoughts in WLWHA in the DR by examining the relationship between depression, perceived HIV-related stigma from the community (PSC), perceived HIV-related stigma from family (PSF) and IS. The Internalized AIDS-Related Stigma Scale (IA-RSS), the Center for Epidemiologic Studies Short Depression Scale (CES-D 10), and an instrument designed to measure perceived HIV-related stigma from the community and family was administered to 233 WLWHA in Puerto Plata, DR. Data were analyzed using descriptive statistics and ordered multiple logistic regression. Results showed that depression (OR=1.60; p<0.05), PSC (OR=3.68; p<0.001), and PSF (OR=1.60; p<0.01) were positively associated with IS. These findings indicate that IS-reducing interventions should address HIV-related depression. Additionally, HIV-related treatment and care services should work with WLWHA to adopt healthier attitudes about how community members view people living with HIV/AIDS in the Dominican Republic. PMID:26466239

  14. Circulating Mediators of Inflammation and Immune Activation in AIDS-Related Non-Hodgkin Lymphoma

    PubMed Central

    Nolen, Brian M.; Breen, Elizabeth Crabb; Bream, Jay H.; Jenkins, Frank J.; Kingsley, Lawrence A.; Rinaldo, Charles R.; Lokshin, Anna E.

    2014-01-01

    Background Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation. Methods This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed bead-based immunoassays. Results A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers. Conclusions These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease. PMID:24922518

  15. ESO Diffuse Interstellar Bands Large Exploration Survey (EDIBLES) - Merging Observations and Laboratory Data

    NASA Technical Reports Server (NTRS)

    Salama, Farid

    2016-01-01

    The Diffuse Interstellar Bands (DIBs) are a set of 500 absorption bands that are detected in the spectra of stars with interstellar clouds in the line of sight. DIBs are found from the NUV to the NIR in the spectra of reddened stars spanning different interstellar environments in our local, and in other galaxies. DIB carriers are a significant part of the interstellar chemical inventory. They are stable and ubiquitous in a broad variety of environments and play a unique role in interstellar physics/chemistry. It has long been realized that the solving of the DIB problem requires a strong synergy between astronomical observations, laboratory astrophysics, and astrophysical modeling of line-of-sights. PAHs are among the molecular species that have been proposed as DIB carriers. We will present an assessment of the PAH-DIB model in view of the progress and the advances that have been achieved over the past years through a series of studies involving astronomical observations of DIBs, laboratory simulation of interstellar analogs for neutrals and ionized PAHs, theoretical calculations of PAH spectra and the modelization of diffuse and translucent interstellar clouds. We will present a summary of what has been learned from these complementary studies, the constraints that can now be derived for the PAHs as DIB carriers in the context of the PAH-DIB model and how these constraints can be applied to the EDIBLES project. The spectra of several neutral and ionized PAHs isolated in the gas phase at low temperature have been measured in the laboratory under experimental conditions that mimic interstellar conditions and are compared with an extensive set of astronomical spectra of reddened, early type stars. The comparisons of astronomical and laboratory data provide upper limits for the abundances of specific neutral PAH molecules and ions along specific lines-of-sight. Something that is not attainable from infrared observations alone. We present the characteristics of the

  16. Methodologies for the Analysis of Instantaneous Lipid Diffusion in MD Simulations of Large Membrane Systems

    PubMed Central

    Chavent, Matthieu; Reddy, Tyler; Goose, Joseph; Dahl, Anna Caroline E.; Stone, John E.; Jobard, Bruno; Sansom, Mark S.P.

    2014-01-01

    Interactions between lipids and membrane proteins play a key role in determining the nanoscale dynamic and structural properties of biological membranes. Molecular dynamics (MD) simulations provide a valuable tool for studying membrane models, complementing experimental approaches. It is now possible to simulate large membrane systems, such as simplified models of bacterial and viral envelope membranes. Consequently, there is a pressing need to develop tools to visualize and quantify the dynamics of these immense systems, which typically are comprised of millions of particles. To tackle this issue, we have developed visual and quantitative analyses of molecular positions and their velocity field using path line, vector field and streamline techniques. This allows us to highlight large, transient flow-like movements of lipids and to better understand crowding within the lipid bilayer. The current study focuses on visualization and analysis of lipid dynamics. However, the methods are flexible and can be readily applied to e.g. proteins and nanoparticles within large complex membranes. The protocols developed here are readily accessible both as a plugin for the molecular visualization program VMD and as a module for the MDAnalysis library. PMID:25341001

  17. Large deviations of the current in a two-dimensional diffusive system

    SciTech Connect

    Perez-Espigares, C.; Pozo, J. J. del; Garrido, P. L.; Hurtado, P. I.

    2011-03-24

    In this notes we study the large deviations of the time-averaged current in the two-dimensional (2D) Kipnis-Marchioro-Presutti model of energy transport when subject to a boundary gradient. We use the tools of hydrodynamic fluctuation theory, supplemented with an appropriate generalization of the additivity principle. As compared to its one-dimensional counterpart, which amounts to assume that the optimal profiles responsible of a given current fluctuation are time-independent, the 2D additivity conjecture requires an extra assumption, i.e. that the optimal, divergence-free current vector field associated to a given fluctuation of the time-averaged current is in fact constant across the system. Within this context we show that the current distribution exhibits in general non-Gaussian tails. The ensuing optimal density profile can be either monotone for small current fluctuations, or non-monotone with a single maximum for large enough current deviations. Furthermore, this optimal profile remains invariant under arbitrary rotations of the current vector, providing a detailed example of the recently introduced Isometric Fluctuation Relation.

  18. Large fluctuations of the macroscopic current in diffusive systems: a numerical test of the additivity principle.

    PubMed

    Hurtado, Pablo I; Garrido, Pedro L

    2010-04-01

    Most systems, when pushed out of equilibrium, respond by building up currents of locally conserved observables. Understanding how microscopic dynamics determines the averages and fluctuations of these currents is one of the main open problems in nonequilibrium statistical physics. The additivity principle is a theoretical proposal that allows to compute the current distribution in many one-dimensional nonequilibrium systems. Using simulations, we validate this conjecture in a simple and general model of energy transport, both in the presence of a temperature gradient and in canonical equilibrium. In particular, we show that the current distribution displays a Gaussian regime for small current fluctuations, as prescribed by the central limit theorem, and non-Gaussian (exponential) tails for large current deviations, obeying in all cases the Gallavotti-Cohen fluctuation theorem. In order to facilitate a given current fluctuation, the system adopts a well-defined temperature profile different from that of the steady state and in accordance with the additivity hypothesis predictions. System statistics during a large current fluctuation is independent of the sign of the current, which implies that the optimal profile (as well as higher-order profiles and spatial correlations) are invariant upon current inversion. We also demonstrate that finite-time joint fluctuations of the current and the profile are well described by the additivity functional. These results suggest the additivity hypothesis as a general and powerful tool to compute current distributions in many nonequilibrium systems.

  19. Large fluctuations of the macroscopic current in diffusive systems: A numerical test of the additivity principle

    NASA Astrophysics Data System (ADS)

    Hurtado, Pablo I.; Garrido, Pedro L.

    2010-04-01

    Most systems, when pushed out of equilibrium, respond by building up currents of locally conserved observables. Understanding how microscopic dynamics determines the averages and fluctuations of these currents is one of the main open problems in nonequilibrium statistical physics. The additivity principle is a theoretical proposal that allows to compute the current distribution in many one-dimensional nonequilibrium systems. Using simulations, we validate this conjecture in a simple and general model of energy transport, both in the presence of a temperature gradient and in canonical equilibrium. In particular, we show that the current distribution displays a Gaussian regime for small current fluctuations, as prescribed by the central limit theorem, and non-Gaussian (exponential) tails for large current deviations, obeying in all cases the Gallavotti-Cohen fluctuation theorem. In order to facilitate a given current fluctuation, the system adopts a well-defined temperature profile different from that of the steady state and in accordance with the additivity hypothesis predictions. System statistics during a large current fluctuation is independent of the sign of the current, which implies that the optimal profile (as well as higher-order profiles and spatial correlations) are invariant upon current inversion. We also demonstrate that finite-time joint fluctuations of the current and the profile are well described by the additivity functional. These results suggest the additivity hypothesis as a general and powerful tool to compute current distributions in many nonequilibrium systems.

  20. A mass-conserved diffuse interface method and its application for incompressible multiphase flows with large density ratio

    NASA Astrophysics Data System (ADS)

    Wang, Y.; Shu, C.; Shao, J. Y.; Wu, J.; Niu, X. D.

    2015-06-01

    In this work a mass-conserved diffuse interface method is proposed for simulating incompressible flows of binary fluids with large density ratio. In the method, a mass correction term is introduced into the Cahn-Hilliard equation to compensate the mass losses or offset the mass increases caused by the numerical and modeling diffusion. Since the mass losses or increases are through the phase interfaces and at each time step, their values are very small, to keep mass conservation, mass sources or sinks are introduced and uniformly distributed in the volume of diffuse layer. With the uniform distribution, the mass correction term representing mass sources or sinks is derived analytically by applying mass conservation principle. By including the mass correction, the modified Cahn-Hilliard equation is solved by the fifth-order upwind scheme to capture the phase field of the bindery fluids. The flow field is simulated by the newly-developed multiphase lattice Boltzmann flux solver [20]. The proposed approach is validated by simulating the Laplace law, the merging of two bubbles, Rayleigh-Taylor instability and bubble rising under gravity with density ratio of 1000 and viscosity ratio of 100. Numerical results of interface shapes and flow properties agree well with both analytical solutions and benchmark data in the literature. Numerical results also show that the mass is well-conserved in all cases considered. In addition, it is demonstrated that the mass correction term at each time step is in the order of 10-4 ∼10-5, which is a small number compared with the magnitude of order parameter.

  1. Development of Spray on Bag for manufacturing of large composites parts: Diffusivity analysis

    NASA Astrophysics Data System (ADS)

    Dempah, Maxime Joseph

    Bagging materials are utilized in many composites manufacturing processes. The selection is mainly driven by cost, temperature requirements, chemical compatibility and tear properties of the bag. The air barrier properties of the bag are assumed to be adequate or in many cases are not considered at all. However, the gas barrier property of a bag is the most critical parameter, as it can negatively affect the quality of the final laminate. The barrier property is a function of the bag material, uniformity, thickness and temperature. Improved barrier properties are needed for large parts, high pressure consolidated components and structures where air stays entrapped on the part surface. The air resistance property of the film is defined as permeability and is investigated in this thesis. A model was developed to evaluate the gas transport through the film and an experimental cell was implemented to characterize various commercial films. Understanding and characterizing the transport phenomena through the film allows optimization of the bagging material for various manufacturing processes. Spray-on-Bag is a scalable alternative bagging method compared to standard films. The approach allows in-situ fabrication of the bag on large and complex geometry structures where optimization of the bag properties can be varied on a local level. An experimental setup was developed and implemented using a six axis robot and an automated spraying system. Experiments were performed on a flat surface and specimens were characterized and compared to conventional films. Air barrier properties were within range of standard film approaches showing the potential to fabricate net shape bagging structures in an automated process.

  2. A cyclin D1-positive diffuse large B-cell lymphoma of germinal center B-cell-like subtype in the right tonsil

    PubMed Central

    Jiang, Changrui; Shi, Xiuying; Fan, Chuifeng

    2017-01-01

    Abstract Introduction: Cyclin D1-positive tumor cells are commonly found in mantle cell lymphoma but they are very rare in diffuse large B-cell lymphoma. Clinical findings/Patient concerns: Here we present a rare case of cyclin D1-positive diffuse large B-cell lymphoma in the right tonsil of a 50-year-old man. Computed tomographic imaging detected a mass, about 2.5 cm × 1.8 cm in size, in the left side of the oropharynx. Diagnoses: Microscopically, the tumor cells were located under the pharyngeal mucosa and diffusely arranged. The tumor cells were large, with marked nuclear atypia. On performing immunohistochemistry, the tumor cells showed diffuse positive staining for CD10, CD20, cyclin D1, and Pax-5, and negative staining for CD3, CD15, CD30, CD56, and CK. Bcl-6 and Mum-1 expression were observed in 60% and 80% of tumor cells, respectively. The tumor Ki67 index was about 60%. Based on these findings, The tumor was diagnosed as a rare cyclin D1-positive diffuse large B-cell lymphoma rather than a mantle cell lymphoma. Conclusion: Cyclin D1-positive large B-cell lymphoma is rare, but as large B-cell lymphoma is a common type of lymphoma, cyclin D1-positive large B-cell lymphoma should be considered a major possibility during differential diagnosis, including in the tonsils. PMID:28296741

  3. Diffuse large B-cell lymphoma occurring in an ovarian cystic teratoma: expanding the spectrum of large B-cell lymphoma associated with chronic inflammation.

    PubMed

    Valli, Riccardo; Froio, Elisabetta; Alvarez de Celis, Maria Isabel; Mandato, Vincenzo Dario; Piana, Simonetta

    2014-12-01

    Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is a well-recognized entity, originally recorded as pyothorax-associated lymphoma because of the association with artificial pneumothorax. Clinically, it is characterized by a mass arising in a long-standing inflammation and by a poor prognosis. Recently, DLBCL-CI has been described growing along the wall of a preexisting cyst, without forming a mass. Here we describe a case of DLBCL-CI arising in the wall of a mature cystic teratoma of the ovary. On histology, the cystic surface of the cyst was infiltrated by large lymphocytes, immunoreacting with CD20, Multiple Myeloma Oncogene-1/Interferon Regulating Factor-4 (MUM1/IRF4), and PAX5 and positive for Epstein-Barr virus. "Cystic" DLBCL-CIs usually hold an indolent behavior despite heterogeneous therapeutic approaches. Some authors understandably wonder whether patients affected by "cystic" DLBCL-CIs are at risk for overtreatment, and, consequently, DLBCL-CIs associated with cystic lesions should be classified as an entity separated from classic pyothorax-associated lymphomas.

  4. Diabetes insipidus due to herpes encephalitis in a patient with diffuse large cell lymphoma. A case report.

    PubMed

    Scheinpflug, K; Schalk, E; Reschke, K; Franke, A; Mohren, M

    2006-01-01

    The major causes of central diabetes insipidus are neoplastic or infiltrative lesions of the hypothalamus or pituitary, severe head injuries and pituitary or hypothalamic surgery. Central diabetes insipidus caused by viral infections has been rarely reported in immunosuppressed patients, such as those with acquired immunodeficiency syndrome or Cushing's syndrome. We report the case of a 48-year-old woman suffering from diffuse large cell lymphoma, who developed hypotonic polyuria, hypernatriaemia and somnolence after the first course of chemotherapy with CHOEP and rituximab. Diabetes insipidus was diagnosed by low urine osmolarity and an undetectable vasopressin concentration. MRI revealed no pituitary abnormalities but encephalitis, and lumbar punction confirmed herpes zoster infection. To the best of our knowledge this is the first description of central diabetes insipidus in a lymphoma patient caused by an opportunistic CNS-infection.

  5. Diffuse large B-cell lymphoma of the adrenal gland: a rare cause of primary adrenal insufficiency.

    PubMed

    de Sousa Lages, Adriana; Bastos, Margarida; Oliveira, Patrícia; Carrilho, Francisco

    2016-03-18

    Although it is a rare entity, primary lymphoma of the adrenal gland should be considered in the differential diagnosis of bilateral nodular adrenal lesions, particularly when there is evidence of associated adrenal insufficiency. We describe the case of an 83-year-old woman admitted to the emergency department due to a month's history of asthenia, weight loss, anorexia and nausea. Abdominopelvic CT showed bilateral nodular lesions of adrenal glands and a stimulation test with tetracosactide was compatible with primary adrenal insufficiency. CT-guided biopsy of the left adrenal gland was performed, and histopathological results were consistent with diffuse large B-cell lymphoma. Positron emission tomography (18)F-fluorodeoxyglucose detected two intensely hypermetabolic lesions limited to both adrenal glands. Replacement therapy with hydrocortisone 15 mg/day and fludrocortisone 0.1 mg/day was promptly started and chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone was initiated after haematology-oncology consultation.

  6. STAT3 inhibition is a therapeutic strategy for ABC-like diffuse large B-cell lymphoma.

    PubMed

    Scuto, Anna; Kujawski, Maciej; Kowolik, Claudia; Krymskaya, Ludmila; Wang, Lin; Weiss, Lawrence M; Digiusto, David; Yu, Hua; Forman, Stephen; Jove, Richard

    2011-05-01

    Persistent STAT3 signaling contributes to malignant progression in many diverse types of human cancer. STAT3 is constitutively active in activated B-cell (ABC)-like diffuse large B-cell lymphomas (DLBCL), a class of nongerminal center derived DLBCL cells for which existing therapy is weakly effective. In this report, we provide a preclinical proof of concept that STAT3 is an effective molecular target for ABC-like DLBCL therapy. Direct inhibition of STAT3 with short hairpin RNA suppressed the growth of human ABC-like DLBCL in mouse models in a manner associated with apoptosis, repression of STAT3 target genes, and inhibition of a tumor-promoting microenvironment. Together, these results suggest that STAT3 is essential to maintain the pathophysiology of ABC-like DLBCL and therefore that STAT3 inhibition may offer a promising approach in its therapy.

  7. Case Report of Diffuse Large B Cell Lymphoma of Uterine Cervix Treated at a Semiurban Cancer Centre in North India

    PubMed Central

    Sridhar, Epari

    2016-01-01

    Lymphoma of the uterine cervix is very rare. We report a case of diffuse large B cell lymphoma (DLBCL) involving the uterine cervix treated at a newly commissioned semiurban cancer centre in north India in 2015. Data for this study was obtained from the hospital electronic medical records and the patient's case file. We also reviewed published case reports of uterine and cervical lymphoma involving forty-one patients. We treated a case of stage IV DLBCL cervix with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) and intrathecal methotrexate followed by consolidation with radiotherapy. The patient showed complete response to chemotherapy. We conclude that, in advanced stage lymphoma involving uterus and cervix, combination of chemotherapy and radiotherapy is effective in short term. PMID:27597906

  8. A Case of Rectal Squamous Cell Carcinoma with Metachronous Diffuse Large B Cell Lymphoma in an HIV-Infected Patient.

    PubMed

    Choi, Heun; Lee, Hye Won; Ann, Hea Won; Kim, Jae Kyung; Kang, Hua Pyong; Kim, Sun Wook; Ku, Nam Su; Han, Sang Hoon; Kim, June Myung; Choi, Jun Yong

    2014-12-01

    Diffuse large B cell lymphoma (DLBCL) is one of the most common acquired immune deficiency syndrome (AIDS)-defining malignancies among human immunodeficiency virus-infected patients, and rectal cancer has recently emerged as a prevalent non-AIDS-defining malignancy. We report a case of rectal squamous cell carcinoma that was metachronous with DLBCL in an HIV-infected patient who was receiving highly active antiretroviral therapy. The patient was diagnosed with DLBCL and showed complete remission after chemotherapy. Follow-up imaging showed increased uptake at the rectum, previously treated as lymphoma. Repeated biopsy was performed and squamous cell carcinoma of the rectum was reported. After concurrent chemoradiation therapy, curative resection was performed.

  9. Molecular subtyping of diffuse large B-cell lymphoma: update on biology, diagnosis and emerging platforms for practising pathologists.

    PubMed

    Gifford, Grace K; Gill, Anthony J; Stevenson, William S

    2016-01-01

    Molecular classification of diffuse large B-cell lymphoma (DLBCL) is critical. Numerous methodologies have demonstrated that DLBCL is biologically heterogeneous despite morphological similarities. This underlies the disparate outcomes of treatment response or failure in this common non-Hodgkin lymphoma. This review will summarise historical approaches to lymphoma classifications, current diagnosis of DLBCL, molecular techniques that have primarily been used in the research setting to distinguish and subclassify DLBCL, evaluate contemporary diagnostic methodologies that seek to translate lymphoma biology into clinical practice, and introduce novel diagnostic platforms that may overcome current issues. The review concludes with an overview of key molecular lesions currently identified in DLBCL, all of which are potential targets for drug treatments that may improve survival and cure.

  10. Multifocal Gastric Ulcers Caused by Diffuse Large B Cell Lymphoma in a Patient With Significant Weight Loss

    PubMed Central

    Gromski, Mark A.; Peng, Jennifer L.; Zhou, Jiehao; Masuoka, Howard C.; Suvannasankha, Attaya; Liangpunsakul, Suthat

    2016-01-01

    Primary gastrointestinal (GI) lymphoma is a heterogeneous disease with varied clinical presentations. The stomach is the most common GI site and accounts for 70% to 75% of GI lymphomas. We present a patient with gastric diffuse large B cell lymphoma (DLBCL) who presented with significant weight loss, early satiety, and multifocal ulcerated gastric lesions. Esophagoduodenoscopy should be performed in patients presenting with warning symptoms as in our case. Diagnosis is usually made by endoscopic biopsies. Multiple treatment modalities including surgery, radiotherapy, and chemotherapy have been used. Advancements in endoscopic and pathologic technology decrease turnaround time for diagnosis and treatment initiation, thus reducing the need for surgery. Health care providers should maintain a high level of suspicion and consider gastric DLBCL as part of the differential diagnosis, especially in those with warning symptoms such as weight loss and early satiety with abnormal endoscopic findings. PMID:28203570

  11. Central nervous system involvement in adult patients with diffuse large B-cell lymphoma: Influence of rituximab

    PubMed Central

    CAO, BING; ZHOU, XIAOYAN; JI, DONGMEI; CAO, JUNNING; GUO, YE; ZHANG, QUNLING; WU, XIANGHUA; LI, JUNMIN; WANG, JIANMIN; CHEN, FANGYUAN; WANG, CHUN; ZOU, SHANHUA; HONG, XIAONAN

    2012-01-01

    CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like chemotherapy, in combination with rituximab (R-CHOP-like), improves outcome in patients with diffuse large B-cell lymphoma (DLBCL). We aimed to investigate the impact of rituximab on central nervous system (CNS) disease in adult patients. We studied 315 patients (aged 18–60 years old) from six hospitals between July 2003 and May 2008. All patients received CHOP-like (n=165) or R-CHOP-like (n=150) regimen every 3 weeks. With a median follow-up of 3.69 years, 10 patients (3.17%) developed CNS disease. The cumulative risk of CNS occurrence was not significantly different between the two treatment groups (P=0.871). We conclude that the addition of rituximab did not reduce the risk of CNS disease in adult patients with DLBCL. PMID:22970053

  12. Primary Diffuse Large B-Cell Lymphoma Localized to the Lacrimal Sac: A Case Presentation and Review of the Literature

    PubMed Central

    Yim, Brandom; Gabig, Theodore G.

    2016-01-01

    We report a rare case of diffuse large B-cell lymphoma (DLBCL) of the lacrimal sac in a 50-year-old male. The incidence of primary ocular lymphoma is low and it is considered a rare disease. Moreover, reports of ocular DLBCL are uncommon and the disease remains poorly characterized. Our patient presented for management of osteomyelitis and was incidentally found to have a painless swelling and cyst around his right eye. A PET/CT scan revealed hypermetabolic activity within the lacrimal sac and a subsequent excisional biopsy of the mass yielded histopathology consistent with DLBCL. Consequently, the patient underwent treatment with R-CHOP therapy. The patient responded well to chemotherapy with a substantial shrinkage in tumor burden and the disease remained localized. Herein, we present a rare case of primary ocular lymphoma, highlight the importance of early diagnosis, and review current treatment modalities. PMID:27672460

  13. Primary Diffuse Large B-Cell Lymphoma Localized to the Lacrimal Sac: A Case Presentation and Review of the Literature.

    PubMed

    Zarrabi, Kevin; Desai, Ved; Yim, Brandom; Gabig, Theodore G

    2016-01-01

    We report a rare case of diffuse large B-cell lymphoma (DLBCL) of the lacrimal sac in a 50-year-old male. The incidence of primary ocular lymphoma is low and it is considered a rare disease. Moreover, reports of ocular DLBCL are uncommon and the disease remains poorly characterized. Our patient presented for management of osteomyelitis and was incidentally found to have a painless swelling and cyst around his right eye. A PET/CT scan revealed hypermetabolic activity within the lacrimal sac and a subsequent excisional biopsy of the mass yielded histopathology consistent with DLBCL. Consequently, the patient underwent treatment with R-CHOP therapy. The patient responded well to chemotherapy with a substantial shrinkage in tumor burden and the disease remained localized. Herein, we present a rare case of primary ocular lymphoma, highlight the importance of early diagnosis, and review current treatment modalities.

  14. Machine Learning-based Classification of Diffuse Large B-cell Lymphoma Patients by Their Protein Expression Profiles

    PubMed Central

    Deeb, Sally J.; Tyanova, Stefka; Hummel, Michael; Schmidt-Supprian, Marc; Cox, Juergen; Mann, Matthias

    2015-01-01

    Characterization of tumors at the molecular level has improved our knowledge of cancer causation and progression. Proteomic analysis of their signaling pathways promises to enhance our understanding of cancer aberrations at the functional level, but this requires accurate and robust tools. Here, we develop a state of the art quantitative mass spectrometric pipeline to characterize formalin-fixed paraffin-embedded tissues of patients with closely related subtypes of diffuse large B-cell lymphoma. We combined a super-SILAC approach with label-free quantification (hybrid LFQ) to address situations where the protein is absent in the super-SILAC standard but present in the patient samples. Shotgun proteomic analysis on a quadrupole Orbitrap quantified almost 9,000 tumor proteins in 20 patients. The quantitative accuracy of our approach allowed the segregation of diffuse large B-cell lymphoma patients according to their cell of origin using both their global protein expression patterns and the 55-protein signature obtained previously from patient-derived cell lines (Deeb, S. J., D'Souza, R. C., Cox, J., Schmidt-Supprian, M., and Mann, M. (2012) Mol. Cell. Proteomics 11, 77–89). Expression levels of individual segregation-driving proteins as well as categories such as extracellular matrix proteins behaved consistently with known trends between the subtypes. We used machine learning (support vector machines) to extract candidate proteins with the highest segregating power. A panel of four proteins (PALD1, MME, TNFAIP8, and TBC1D4) is predicted to classify patients with low error rates. Highly ranked proteins from the support vector analysis revealed differential expression of core signaling molecules between the subtypes, elucidating aspects of their pathobiology. PMID:26311899

  15. Machine Learning-based Classification of Diffuse Large B-cell Lymphoma Patients by Their Protein Expression Profiles.

    PubMed

    Deeb, Sally J; Tyanova, Stefka; Hummel, Michael; Schmidt-Supprian, Marc; Cox, Juergen; Mann, Matthias

    2015-11-01

    Characterization of tumors at the molecular level has improved our knowledge of cancer causation and progression. Proteomic analysis of their signaling pathways promises to enhance our understanding of cancer aberrations at the functional level, but this requires accurate and robust tools. Here, we develop a state of the art quantitative mass spectrometric pipeline to characterize formalin-fixed paraffin-embedded tissues of patients with closely related subtypes of diffuse large B-cell lymphoma. We combined a super-SILAC approach with label-free quantification (hybrid LFQ) to address situations where the protein is absent in the super-SILAC standard but present in the patient samples. Shotgun proteomic analysis on a quadrupole Orbitrap quantified almost 9,000 tumor proteins in 20 patients. The quantitative accuracy of our approach allowed the segregation of diffuse large B-cell lymphoma patients according to their cell of origin using both their global protein expression patterns and the 55-protein signature obtained previously from patient-derived cell lines (Deeb, S. J., D'Souza, R. C., Cox, J., Schmidt-Supprian, M., and Mann, M. (2012) Mol. Cell. Proteomics 11, 77-89). Expression levels of individual segregation-driving proteins as well as categories such as extracellular matrix proteins behaved consistently with known trends between the subtypes. We used machine learning (support vector machines) to extract candidate proteins with the highest segregating power. A panel of four proteins (PALD1, MME, TNFAIP8, and TBC1D4) is predicted to classify patients with low error rates. Highly ranked proteins from the support vector analysis revealed differential expression of core signaling molecules between the subtypes, elucidating aspects of their pathobiology.

  16. Cross-correlation of diffuse synchrotron and large-scale structures

    NASA Astrophysics Data System (ADS)

    Brown, Shea; Farnsworth, Damon; Rudnick, Lawrence

    2010-02-01

    We explore for the first time the method of cross-correlation of radio synchrotron emission and tracers of large-scale structure in order to detect the warm-hot intergalactic medium (WHIM). We performed a cross-correlation of a 34° × 34° area of Two-Micron All-Sky Survey (2MASS) galaxies for two redshift slices (0.03 < z < 0.04 and 0.06 < z < 0.07) with the corresponding region of the 1.4 GHz Bonn survey. For this analysis, we assumed that the synchrotron surface brightness is linearly proportional to surface density of galaxies. We also sampled the cross-correlation function (CCF) using 24 distant fields of the same size from the Bonn survey, to better assess the noise properties. Though we obtained a null result, we found that by adding a signal weighted by the 2MASS image with a filament (peak) surface brightness of 1 (7) and 7 (49) mK would produce a 3σ positive correlation for the 0.03 < z < 0.04 and 0.06 < z < 0.07 redshift slices, respectively. These detection thresholds correspond to minimum energy magnetic fields as low as 0.2 μG, close to some theoretical expectations for filament field values. This injected signal is also below the rms noise of the Bonn survey, and demonstrates the power of this technique and its utility for upcoming sensitive continuum surveys such as those planned with the Murchison Widefield Array.

  17. HIV/AIDS related knowledge among school-going adolescents from the Middle East and North Africa.

    PubMed

    Boneberger, Anja; Rückinger, Simon; Guthold, Regina; Kann, Laura; Riley, Leanne

    2012-05-01

    The aim of this secondary analysis was to present cross-national data about HIV/AIDS related knowledge among 13- to 15-year-old school-going adolescents from the Middle East and North Africa. Data from 23673 school-going adolescents from seven countries (Jordan, Lebanon, Libyan Arab Jamahiriya, Morocco, Oman, Tunisia and United Arab Emirates) that undertook the Global School-Based Student Health Survey between 2004 and 2008 were analysed. HIV/AIDS related knowledge varied significantly between countries and gender. Research for this sensitive topic is scarce in this region. In addition, schools could be among the many key players for HIV/AIDS education.

  18. Women's voices: attitudes and behaviors of female Ghanaian sex workers regarding HIV prevention and AIDS-related stigma.

    PubMed

    Raingruber, Bonnie; Uwazie, Ernest; Bowie, Sylvester

    2010-08-01

    Attitudes and behaviors of sex workers have a pivotal influence on the spread of AIDS. A qualitative descriptive study was undertaken to elicit Ghanaian female sex workers' perspectives regarding effective methods of HIV prevention, sources of AIDS-related stigma, and challenges associated with sex work. Women described that: (1) sex work is hard; (2) they felt God would protect their health; (3) staying safe is both a gift and a priority; (4) sex work allows for autonomy; and (5) AIDS-related stigma is very real. To design effective prevention programs it is necessary to consider the culture and perspectives of those who will be served.

  19. Fibrin-associated EBV-positive Large B-Cell Lymphoma: An Indolent Neoplasm With Features Distinct From Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation.

    PubMed

    Boyer, Daniel F; McKelvie, Penelope A; de Leval, Laurence; Edlefsen, Kerstin L; Ko, Young-Hyeh; Aberman, Zachary A; Kovach, Alexandra E; Masih, Aneal; Nishino, Ha T; Weiss, Lawrence M; Meeker, Alan K; Nardi, Valentina; Palisoc, Maryknoll; Shao, Lina; Pittaluga, Stefania; Ferry, Judith A; Harris, Nancy Lee; Sohani, Aliyah R

    2017-03-01

    Incidental cases of localized fibrin-associated Epstein-Barr virus (EBV)+ large B-cell proliferations have been described at unusual anatomic sites and have been included in the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) in the WHO Classification. We describe 12 cases and review the literature to define their clinicopathologic spectrum and compare features with typical cases of DLBCL-CI. Median age was 55.5 years with a M:F ratio of 3. In all 12 cases, the lymphoma was an incidental microscopic finding involving atrial myxomas (n=3), thrombi associated with endovascular grafts (n=3), chronic hematomas (n=2), and pseudocysts (n=4). All cases tested were nongerminal center B-cell origin, type III EBV latency, and were negative for MYC rearrangements and alternative lengthening of telomeres by FISH. Most showed high CD30, Ki67, and PD-L1, and low to moderate MYC and p53 expression. Among 11 patients with detailed follow-up, 6 were treated surgically, 3 with cardiac or vascular lesions had persistent/recurrent disease at intravascular sites, and 4 died of causes not directly attributable to lymphoma. Reports of previously published fibrin-associated cases showed similar features, whereas traditional DLBCL-CI cases with a mass lesion had significantly higher lymphoma-associated mortality. Fibrin-associated EBV+ large B-cell lymphoma is clinicopathologically distinct from DLBCL-CI, warranting separate classification. Most cases, particularly those associated with pseudocysts, behave indolently with the potential for cure by surgery alone and may represent a form of EBV+ lymphoproliferative disease rather than lymphoma. However, primary cardiac or vascular disease may have a higher risk of recurrence despite systemic chemotherapy.

  20. Expression of TRAF1 and nuclear c-Rel distinguishes primary mediastinal large cell lymphoma from other types of diffuse large B-cell lymphoma.

    PubMed

    Rodig, Scott J; Savage, Kerry J; LaCasce, Ann S; Weng, Andrew P; Harris, Nancy L; Shipp, Margaret A; Hsi, Eric D; Gascoyne, Randy D; Kutok, Jeffery L

    2007-01-01

    Primary mediastinal large B-cell lymphoma (PMLBCL) is a recently identified subtype of diffuse large B-cell lymphoma (DLBCL) that is difficult to distinguish from other types of DLBCL on the basis of histologic features alone. We recently identified a molecular signature of PMLBCL that is distinct from other forms of DLBCL but shares features with classical Hodgkin lymphoma. This signature includes activation of the nuclear factor kappaB (NFkappaB) signaling pathway, which in part, acts through nuclear translocation of c-Rel containing NFkappaB transcriptional complexes, and subsequent expression of NFkappaB target genes such as tumor necrosis factor receptor-associated factor-1 (TRAF1). Using standard immunohistochemical techniques, we examined 251 large B-cell lymphomas (78 cases of PMLBCL and 173 cases of other types of DLBCL) to determine whether the expression patterns of c-Rel and TRAF1 could reliably distinguish between PMLBCL and other types of DLBCL. Robust nuclear c-Rel was present in 31 of 48 (65%) cases of PMLBCL and 28 of 160 (18%) cases of DLBCL. In addition, cytoplasmic TRAF1 expression was seen in 48 of 78 (62%) cases of PMLBCL, but only 20 of 173 (12%) cases of DLBCL. Finally, the combined expression of nuclear c-Rel and TRAF1 was seen in 24 of 45 cases (53%) of PMLBCL, but in only 3 of 156 cases (2%) of other types of DLBCL. Thus, the combined nuclear localization of c-Rel and the cellular expression of TRAF1 is a highly specific (specificity=98%) means to distinguish PMLBCL from DLBCL that is readily applicable to routine surgical pathology practice.

  1. [Successful discontinuation of antifungal secondary prophylaxis in AIDS-related cryptococcosis].

    PubMed

    Negroni, R; Helou, S H; López Daneri, G; Robles, A M; Arechavala, A I; Bianchi, M H

    2004-01-01

    The clinical and laboratory data of 22 patients with AIDS related cryptococcosis who were able to interrupt antifungal secondary prophylaxis after HAART administration, are presented. They were 14 males and 8 females, between 15 and 50 years old (X: 34 years old). All patients presented fever and severe deterioration of their general health status, and 19 exhibited a meningeal syndrome. At the start of antifungal treatment, 59% of the cases presented < 50 CD4+ cells/microl, the median viral burden was 134,804 RNA copies/ml and the median titer of serum cryptococcal antigen was 1/3,000. Amphotericin B by intravenous route, (0.7 mg/kg/day) or fluconazole (600 to 800 mg/day) were given as a treatment of the initial episode, up to CSF cultures negativization. Oral fluconazole (200 mg/day) or intravenous amphotericin B, 50 mg twice a week, were given as a secondary prophylaxis. The secondary prophylaxis was interrupted when the patients had received HAART for an average lapse of 19 months (6 to 36 months) and the median CD4+ cell count was 249/microl. The follow up after secondary prophylaxis discontinuation lasted for a median lapse of 22 months. These data seem to show that secondary prophylaxis is not necessary when the patient are clinically asymptomatic and the CD4+ cell counts are above 150/microl.

  2. AIDS as social construction: text mining of AIDS-related information in the Italian press.

    PubMed

    Caputo, Andrea; Giacchetta, Agnese; Langher, Viviana

    2016-09-01

    Given the relevance of AIDS as a public health problem in the Italian context and of the role of mass media in the social construction of the phenomenon, the aim of the present study is twofold: (1) to explore the main AIDS-related themes in the Italian popular press; (2) to analyse the temporal trends of AIDS representations over the last decades. For the research, we decided to consult Italian newspaper articles produced between 1985 and 1990 and between 2005 and 2010 using the archives of the main two national newspapers (La Repubblica and Corriere della Sera), resulting in an overall sample of 446 newspaper articles. A computer-aided content analysis allowed the detection of five different thematic domains (clusters), respectively focused on: Medical care (7.47%), Family support (37.03%), Science and religion debate (27%), Social exclusion (17.6%) and Healthcare policies (10.9%). These thematic domains are conceived along two main latent dimensions (factors) which explain 72.47% of the data variance which respectively deal with: (1) Attitudes towards people with AIDS (care versus avoidance) and (2) Social mandate on AIDS (powerlessness versus control). The study results also reveal the potential evolution of representations of people with AIDS over time: from stigmatised subjects who represent a risk for the entire society within a climate of social control to people progressively symbolised as frail subjects that need to be taken care of.

  3. AIDS-related illness trajectories in Mexico: findings from a qualitative study in two marginalized communities.

    PubMed

    Castro, R; Orozco, E; Eroza, E; Manca, M C; Hernández, J J; Aggleton, P

    1998-10-01

    This paper describes findings from a recent study examining how people affected directly and indirectly by the HIV/AIDS epidemic cope with HIV-related illness in Mexico. One-hundred-and-thirteen in-depth interviews were conducted with key informants in two contrasting communities: Ciudad Netzahualcóyotl (an economically marginalized community) and the gay community in Mexico City (a sexually marginalized community). This paper describes the AIDS-related wellness/illness careers or trajectories followed by individuals in both communities, and identifies critical points for material and emotional intervention. This career comprises four stages: (1) life before infection; (2) life surrounding the discovery of seropositivity; (3) living as an HIV-positive person; and (4) facing death. Comparisons are drawn between the processes of adjustment and coping found in both communities. In Ciudad Netzahualcóyotl, wellness/illness careers are closely linked to prevailing poverty and oppression, as well as the sense of urgency in which local people live their lives. In the case of the gay community, wellness/illness careers are associated with the intolerance and social repression faced by homosexual men. The paper concludes by suggesting possible interventions to improve the lives of people with HIV/AIDS in Mexico today.

  4. Kaposi's sarcoma-associated herpesvirus in non-AIDS related lymphomas occurring in body cavities.

    PubMed Central

    Cesarman, E.; Nador, R. G.; Aozasa, K.; Delsol, G.; Said, J. W.; Knowles, D. M.

    1996-01-01

    DNA sequences belonging to the recently discovered Kaposi's sarcoma-associated herpesvirus (KSHV), now provisionally designated human herpesvirus 8, have been previously identified in an uncommonly occurring subset of AIDS-related lymphomas, referred to as body-cavity-based lymphomas (BCBLs), which present as lymphomatous effusions. Pyothorax-associated lymphomas (PALS) are non-Hodgkin's lymphomas that arise in the pleural cavity after long-standing pleural inflammation resulting from therapeutic artificial pneumothorax or from tuberculosis pleuritis. Although PALs present as solid tumor masses, they are otherwise similar to BCBLs in that they also are B cell lymphomas, usually exhibit immunoblastic morphology, and contain Epstein-Barr virus. We investigated whether KSHV sequences are present in 2 BCBLs in patients without AIDS and 12 in Japanese and 2 French PALs. The 2 BCBLs were positive for KSHV sequences, whereaas all 14 PALs were KSHV negative. This finding strongly suggests that BCBLs and PALs are distinct clinicopathological entities and further strengthens the association between the presence of KSHV and an effusion phenotype. Based on these findings, we propose replacing the term body-cavity-based lymphoma with the term primary effusion lymphoma, which describes these non-Hodgkin's lymphomas more accurately and avoids confusion with other lymphomas that may occur in the body cavities, such as the PALs. Images Figure 1 Figure 2 PMID:8686762

  5. Clinical Analysis of Five Cases of AIDS-related Non-Hodgkin Lymphoma

    PubMed Central

    Zuo, Shubo; Xu, Na; Li, Zhongkun; Li, Na; Xia, Hong; Ren, Hongtao; Bao, Huizheng

    2016-01-01

    Objective: Secondary malignancy is a major life-threatening complication facing patients afflicted with acquired immunodeficiency syndrome (AIDS). This study aimed to retrospectively review clinical features and treatment course of five patients with AIDS-associated non-Hodgkin lymphoma (A-NHL) in Jilin Tumor Hospital. Methods: Five A-NHL patients were retrospectively and consecutively hospitalized at our oncological unit between January 2012 and June 2014. All patients received pre-emptive highly active antiretroviral therapy (HAART) and chemotherapy, and were subsequently followed up at the outpatient clinic. All five patients were male, aged 27–53 years, and afflicted with A-NHL involving upper jaw, right inguinal region, right-side gingiva, mediastinum, or right-side neck. Histology showed diffuse large B-cell lymphoma (n = 3) or plasmablastic lymphoma (n = 2). Results: Two patients achieved complete remission after HAART and chemotherapy, whereas other three patients required a second-line treatment, with two achieving stable disease and one dying within a follow-up period of 0.5−2 years. Conclusion: The findings of the present study showed that A-NHL is a disease often diagnosed in the middle-to-late stages, with diverse clinical manifestations and short overall survival. In the cases reviewed in this study, HAART in combination with standard dose or high-dose chemotherapy, HAART and molecular targeted chemotherapy was administered, and these treatments proved to be effective for improving the prognosis of these patients. Moreover, the CD4+ cell count was important for determining the prognosis of patients. PMID:28083067

  6. All That Wheezes Is Not Asthma: A Case of Diffuse Large B-Cell Lymphoma of the Larynx

    PubMed Central

    2017-01-01

    Localized laryngeal lymphoma is a rare entity with an incidence of less than 1% of all laryngeal neoplasms. Diffuse large B-cell lymphoma (DLBCL) is the most common type of laryngeal neoplasms. Here, we describe a case of a young 28-year-old female with large B-cell lymphoma who remained undiagnosed for a long time owing to a myriad of nonspecific presentation including “wheezing.” Although primary laryngeal lymphomas constitute a diagnostic challenge since they are rare, one should have a high index of suspicion for lymphoma of the larynx in patients presenting with unresolved wheezing as it can present catastrophically with acute airway obstruction requiring immediate surgical intervention which was observed in this case. Treatment includes radiotherapy, chemotherapy, immunotherapy, or a combination of these. We hope that the discussions ensuing from case reports regarding uncommon presentations of laryngeal lymphoma may spur the formation of regional/international databases for the description of lymphomas with unusual presentations. This effort can lead to in-depth study of cases and prompt awareness of “rare and subtle presentations” of laryngeal lymphoma.

  7. Incidentally discovered diffuse large B-cell lymphoma limited to the endocervical mucosa in a young female patient.

    PubMed

    Pósfai, Éva; Nagy, Károly; Marton, Imelda; Bánfalvi, Attila; Kocsis, Lajos; Cserni, Gábor

    2015-01-01

    Primary high-grade non-Hodgkin lymphoma of the female genital tract is extremely rare. Vaginal bleeding, abdominal pain or urinary complaints might be its most frequent symptoms. We report a 27-year-old multipara who underwent large loop excision of the transformation zone because of the repeated finding of a low-grade squamous intraepithelial lesion identified during routine cancer screening. Incidentally, CD20-positive, primary, diffuse large B-cell lymphoma infiltrating the mucosa of the endocervix was also diagnosed from this specimen. The case is unusual because the patient had no symptoms, specific colposcopic signs or visible mass. R-CHOP 21 immunochemotherapy was introduced and resulted in complete remission without hysterectomy. The patient is without any evidence of disease after 49 months of follow-up. Primary cervical lymphomas are mainly subepithelial initially, and therefore they may be under-recognized due to the inefficiency of smears to diagnose such lesions. Early diagnosis and available targeted treatment allowed a cure in the reported example.

  8. Time-resolved diffuse reflectance measurement carried out on the head of an adult at large source-detector separation.

    PubMed

    Liebert, Adam; Sawosz, Piotr; Kacprzak, Michal; Weigl, Wojciech; Botwicz, Marcin; Maniewski, Roman

    2010-01-01

    Multichannel time-resolved optical monitoring system was constructed for measurements of diffuse reflectance in optically turbid medium at very large source-detector separation up to 9 cm. The system is based on femtosecond TiSa laser and sensitive photomultiplier tube detector. The laser light of 300mW of power was delivered to the surface of the head with the use of an optical fiber. A beam expander was applied in order to distribute the laser light on a large spot which allowed to avoid energetic stimulation of the tissue. The photomultiplier tube detector was positioned directly on the surface of the medium at the distance of 9cm from the center of the source position. In this paper we report results of an in-vivo experiment carried out on the head of an adult healthy volunteer. The time-resolved system was applied during intravenous injection of an optical contrast agent (indocyanine green - ICG) and the distributions of times of flight of photons were successfully acquired showing inflow and washout of the dye to the tissue. Time-courses of the moments of distributions of times of flight of photons are presented and compared with the results obtained simultaneously at shorter source-detector separations (3 cm, 4 cm and 5 cm).

  9. A finite element simulation on transient large deformation and mass diffusion in electrodes for lithium ion batteries

    NASA Astrophysics Data System (ADS)

    An, Yonghao; Jiang, Hanqing

    2013-10-01

    Lithium-ion batteries have attracted great deal of attention recently. Silicon is one of the most promising anode materials for high-performance lithium-ion batteries, due to its highest theoretical specific capacity. However, the short lifetime confined by mechanical failure in the silicon anode is now considered to be the biggest challenge in desired applications. High stress induced by the huge volume change due to lithium insertion/extraction is the main reason underlying this problem. Some theoretical models have been developed to address this issue. In order to properly implement these models, we develop a finite element based numerical method using a commercial software package, ABAQUS, as a platform at the continuum level to study fully coupled large deformation and mass diffusion problem. Using this method, large deformation, elasticity-plasticity of the electrodes, various spatial and temporal conditions, arbitrary geometry and dimension could be fulfilled. The interaction between anode and other components of the lithium ion batteries can also be studied as an integrated system. Several specific examples are presented to demonstrate the capability of this numerical platform.

  10. Expression of PD-1 (CD279) and FoxP3 in diffuse large B-cell lymphoma.

    PubMed

    Ahearne, Matthew J; Bhuller, Kaljit; Hew, Roger; Ibrahim, Hazem; Naresh, Kikkeri; Wagner, Simon D

    2014-09-01

    The role of the microenvironment in high-grade lymphoma is not well defined. In this report, we employ immunohistochemistry to characterise programmed death-1 (PD-1/CD279) and FoxP3 expression in 70 cases of diffuse large B-cell lymphoma (DLBCL). PD-1 is a surface marker characteristic of follicular helper T-cells whilst FoxP3 is characteristic of Tregs. We demonstrate variable infiltration with CD4(+) T-cells (<10 to >50 % of all lymph node cells) and PD-1(hi) cells (0.1 to 1.5 % of all cells). CD4(+) T-cells can be distributed in clusters or more diffusely and PD-1(hi) cells, but not FoxP3(+) cells, are found in rosettes around lymphoma cells. Cases with high CD4(+) T-cell numbers tended to have higher numbers of both PD-1(hi) and FoxP3(+) cells. Cases with total CD4(+) T-cell, PD-1(hi) and FoxP3(+) numbers above the median associate with better clinical outcome. Overall, we demonstrate that infiltration by CD4(+) T-cells, including both FoxP3(+) and PD-1(hi) subsets, correlates with prognosis in DLBCL. In distinction to previous reported series, patients (91 %) were treated with rituximab-containing regimens, suggesting that the effects of CD4+ T-cell infiltration are maintained in the rituximab era. This work suggests that determinants of total CD4(+) T-cell infiltration, either molecular characteristics of the lymphoma or the patients' immune system, and not individual T-cell subsets, correlate with clinical outcome.

  11. HIV/AIDS Related Stigma and Discrimination against PLWHA in Nigerian Population

    PubMed Central

    Bulgiba, Awang; Oche, Oche Mansur; Adekunjo, Felix Oluyemi

    2015-01-01

    Background HIV/AIDS remain a major public health concern in Nigeria. People living with HIV/AIDS (PLWHA) face not only personal medical problems but also social problems associated with the disease such as stigma and discriminatory attitudes. This study provides an insight into HIV/AIDS related stigma and discrimination against PLWHA in Nigeria. Methods The data for this study was extracted from the 2013 Nigeria Demographic and Health Survey conducted by the National Population Commission. All men and women aged 15–49 years, permanent residents and visitors of the households were eligible for the interview. Several questionnaires were used in the survey, some covering questions on HIV/AIDS. Results A total of 56 307 men and women aged 15–49 years participated in this national survey. About half of the population in Nigeria have HIV stigma. Younger persons, men, those without formal education and those within poor wealth index are more likely to have stigma towards PLWHA. In addition, married people are more likely to have stigma on PLWHA and are more likely to blame PLWHA for bringing the disease to the community. Also about half of the population discriminates against PLWHA. However, those with higher levels of education and those from higher wealth index seem to be more compassionate towards PLWHA. About 70% in the population are willing to care for relative with AIDS, even more so among those with higher level of education. Conclusion There is a high level of HIV stigma and discrimination against PLWHA in the Nigerian population. Education seems to play a major role in the society with respect to HIV stigma and discrimination against PLWHA. Educating the population with factual information on HIV/AIDS is needed to reduce stigma and discrimination towards PLWHA in the community. PMID:26658767

  12. Knowledge, attitude, and practice of HIV/AIDS-related stigma and discrimination reduction among nursing students in southwest Nigeria

    PubMed Central

    Farotimi, Adekunbi A; Nwozichi, Chinomso Ugochukwu; Ojediran, Tolulope D

    2015-01-01

    Background: One of the reported obstacles to the achievement of universal access to Human Immunodeficiency Virus (HIV) prevention, treatment, care, and support programs includes stigma and discrimination from health workers, particularly nurses. Since nursing students would become future practising nurses and are most likely exposed to caring for people living with HIV/AIDS (PL WHA) during their training, it is of great importance to assess the knowledge, attitude, and practice of student nurses toward the reduction of HIV/AIDS-related stigma and discrimination. Materials and Methods: A descriptive survey research design was used. A total of 150 nursing students were selected using the simple random sampling technique of fish bowl method with replacement. Data were obtained using a self-administered (33-item) validated questionnaire to assess the knowledge, attitude, and practice of student nurses with regard to HIV/AIDS-related stigma and discrimination reduction strategies. Reliability of the tool was tested using Cronbach alpha (R) yielding a reliability value of 0.72. Data collected were analyzed with descriptive statistics of frequencies and percentages. Results: Majority (76.0%) of the respondents were females and 82.7% were married. Respondents were found to have high knowledge (94.0%) of strategies for reducing HIV/AIDS-related stigma and discrimination. Also, 64% had moderate discriminatory attitude, 74% engaged in low discriminatory practice, while 26% engaged in high discriminatory practice. Conclusions: Student nurses had adequate knowledge about strategies for reducing HIV/AIDS-related stigma and discrimination; negative discriminatory attitude toward PLWHA and some form of discriminatory practices exist in participants’ training schools. It is, therefore, recommended that an educational package on reduction of HIV/AIDS-related stigma and discrimination be developed and implemented for the participants. PMID:26793257

  13. Genome-Wide Association Study of Event-Free Survival in Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy

    PubMed Central

    Ghesquieres, Hervé; Slager, Susan L.; Jardin, Fabrice; Veron, Amelie S.; Asmann, Yan W.; Maurer, Matthew J.; Fest, Thierry; Habermann, Thomas M.; Bene, Marie C.; Novak, Anne J.; Mareschal, Sylvain; Haioun, Corinne; Lamy, Thierry; Ansell, Stephen M.; Tilly, Herve; Witzig, Thomas E.; Weiner, George J.; Feldman, Andrew L.; Dogan, Ahmet; Cunningham, Julie M.; Olswold, Curtis L.; Molina, Thierry Jo; Link, Brian K.; Milpied, Noel; Cox, David G.; Salles, Gilles A.; Cerhan, James R.

    2015-01-01

    Purpose We performed a multistage genome-wide association study to identify inherited genetic variants that predict outcome in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Methods We conducted a meta-analysis of two genome-wide association study data sets, one from the LNH2003B trial (N = 540), a prospective clinical trial from the Lymphoma Study Association, and the other from the Molecular Epidemiology Resource study (N = 312), a prospective observational study from the University of Iowa–Mayo Clinic Lymphoma Specialized Program of Research Excellence. Top single nucleotide polymorphisms were then genotyped in independent cohorts of patients from the Specialized Program of Research Excellence (N = 391) and the Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang (GOELAMS) -075 randomized trial (N = 294). We calculated the hazard ratios (HRs) and 95% CIs for event-free survival (EFS) and overall survival (OS) using a log-additive genetic model with adjustment for age, sex, and age-adjusted International Prognostic Index. Results In a meta-analysis of the four studies, the top loci for EFS were marked by rs7712513 at 5q23.2 (near SNX2 and SNCAIP; HR, 1.39; 95% CI, 1.23 to 1.57; P = 2.08 × 10−7), and rs7765004 at 6q21 (near MARCKS and HDAC2; HR, 1.38; 95% CI, 1.22 to 1.57; P = 7.09 × 10−7), although they did not reach conventional genome-wide significance (P = 5 × 10−8). Both rs7712513 (HR, 1.49; 95% CI, 1.29 to 1.72; P = 3.53 × 10−8) and rs7765004 (HR, 1.47; 95% CI, 1.27 to 1.71; P = 5.36 × 10−7) were also associated with OS. In exploratory analyses, a two–single nucleotide polymorphism risk score was highly predictive of EFS (P = 1.78 × 10−12) and was independent of treatment, IPI, and cell-of-origin classification. Conclusion Our study provides encouraging evidence for associations between loci at 5q23.2 and 6q21 with EFS and OS in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

  14. High-resolution copy number analysis of paired normal-tumor samples from diffuse large B cell lymphoma.

    PubMed

    Sebastián, Elena; Alcoceba, Miguel; Martín-García, David; Blanco, Óscar; Sanchez-Barba, Mercedes; Balanzategui, Ana; Marín, Luis; Montes-Moreno, Santiago; González-Barca, Eva; Pardal, Emilia; Jiménez, Cristina; García-Álvarez, María; Clot, Guillem; Carracedo, Ángel; Gutiérrez, Norma C; Sarasquete, M Eugenia; Chillón, Carmen; Corral, Rocío; Prieto-Conde, M Isabel; Caballero, M Dolores; Salaverria, Itziar; García-Sanz, Ramón; González, Marcos

    2016-01-01

    Copy number analysis can be useful for assessing prognosis in diffuse large B cell lymphoma (DLBCL). We analyzed copy number data from tumor samples of 60 patients diagnosed with DLBCL de novo and their matched normal samples. We detected 63 recurrent copy number alterations (CNAs), including 33 gains, 30 losses, and nine recurrent acquired copy number neutral loss of heterozygosity (CNN-LOH). Interestingly, 20 % of cases acquired CNN-LOH of 6p21 locus, which involves the HLA region. In normal cells, there were no CNAs but we observed CNN-LOH involving some key lymphoma regions such as 6p21 and 9p24.1 (5 %) and 17p13.1 (2.5 %) in DLBCL patients. Furthermore, a model with some specific CNA was able to predict the subtype of DLBCL, 1p36.32 and 10q23.31 losses being restricted to germinal center B cell-like (GCB) DLBCL. In contrast, 8p23.3 losses and 11q24.3 gains were strongly associated with the non-GCB subtype. A poor prognosis was associated with biallelic inactivation of TP53 or 18p11.32 losses, while prognosis was better in cases carrying 11q24.3 gains. In summary, CNA abnormalities identify specific DLBCL groups, and we describe CNN-LOH in germline cells from DLBCL patients that are associated with genes that probably play a key role in DLBCL development.

  15. The aberrancy of immunophenotype and immunoglobulin status as indicators of prognosis in B cell diffuse large cell lymphoma.

    PubMed Central

    Spier, C. M.; Grogan, T. M.; Lippman, S. M.; Slymen, D. J.; Rybski, J. A.; Miller, T. P.

    1988-01-01

    To assess the prognostic significance of the immunophenotype in diffuse large cell lymphoma (DLCL), 105 DLCL patients were studied between 1978 and 1987 using a panel of 40 monoclonal antibodies applied to frozen tissue. Eighty-three patients were found to have B cell phenotypes, and 20 patients had T cell phenotypes. Focusing on markers relevant to clinical outcome among B cell LCL showed that lack of expression of the pan B antigens Leu14 and Leu16 were correlated with decreased survival (Leu14, P = 0.01; Leu16, P = 0.06; log-rank). HLA-DR activity also showed that lack of expression of this antigen correlated with poor survival (P = 0.004, log-rank). Kappa light chain immunoglobulin lack of expression showed predictive value for decreased survival as well (P = 0.005, log-rank). Multivariate analyses of known clinically important variables and the immune phenotypes confirm that the loss of HLA-DR and B cell aberrancy are independent factors predicting a poor clinical outcome. Losing some B activation/kappa antigens appears to be a broad biologic phenomenon linking surface antigen lack of expression with decreased survival. This suggests that aberrancy of immunophenotype and immunoglobulin status are key predictors of survival in B-LCL. PMID:3140668

  16. ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans

    PubMed Central

    Hathcock, Karen S.; Padilla-Nash, Hesed M.; Camps, Jordi; Shin, Dong-Mi; Triner, Daniel; Shaffer, Arthur L.; Maul, Robert W.; Steinberg, Seth M.; Gearhart, Patricia J.; Staudt, Louis M.; Morse, Herbert C.; Ried, Thomas

    2015-01-01

    The serine-threonine kinase ataxia-telangiectasia mutated (ATM) plays a central role in maintaining genomic integrity. In mice, ATM deficiency is exclusively associated with T-cell lymphoma development, whereas B-cell tumors predominate in human ataxia-telangiectasia patients. We demonstrate in this study that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early-onset immunoglobulin M+ B-cell lymphomas that do not transplant to immunocompetent mice and that histologically and genetically resemble the activated B cell–like (ABC) subset of human diffuse large B-cell lymphoma (DLBCL). These B-cell lymphomas show considerable chromosomal instability and a recurrent genomic amplification of a 4.48-Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC DLBCL. Of importance, amplification of Malt1 in these lymphomas correlates with their dependence on nuclear factor (NF)-κB, MALT1, and B-cell receptor (BCR) signaling for survival, paralleling human ABC DLBCL. Further, like some human ABC DLBCLs, these mouse B-cell lymphomas also exhibit constitutive BCR-dependent NF-κB activation. This study reveals that ATM protects against development of B-cell lymphomas that model human ABC DLBCL and identifies a potential role for T cells in preventing the emergence of these tumors. PMID:26400962

  17. Depth-correction algorithm that improves optical quantification of large breast lesions imaged by diffuse optical tomography

    PubMed Central

    Tavakoli, Behnoosh; Zhu, Quing

    2011-01-01

    Optical quantification of large lesions imaged with diffuse optical tomography in reflection geometry is depth dependence due to the exponential decay of photon density waves. We introduce a depth-correction method that incorporates the target depth information provided by coregistered ultrasound. It is based on balancing the weight matrix, using the maximum singular values of the target layers in depth without changing the forward model. The performance of the method is evaluated using phantom targets and 10 clinical cases of larger malignant and benign lesions. The results for the homogenous targets demonstrate that the location error of the reconstructed maximum absorption coefficient is reduced to the range of the reconstruction mesh size for phantom targets. Furthermore, the uniformity of absorption distribution inside the lesions improve about two times and the median of the absorption increases from 60 to 85% of its maximum compared to no depth correction. In addition, nonhomogenous phantoms are characterized more accurately. Clinical examples show a similar trend as the phantom results and demonstrate the utility of the correction method for improving lesion quantification. PMID:21639570

  18. Panobinostat acts synergistically with ibrutinib in diffuse large B cell lymphoma cells with MyD88 L265 mutations

    PubMed Central

    Mondello, Patrizia; Brea, Elliott J.; De Stanchina, Elisa; Toska, Eneda; Chang, Aaron Y.; Fennell, Myles; Seshan, Venkatraman; Garippa, Ralph; Scheinberg, David A.; Baselga, José; Wendel, Hans-Guido

    2017-01-01

    Diffuse large B cell lymphoma (DLBCL) frequently harbors genetic alterations that activate the B cell receptor (BCR) and TLR pathways, which converge to activate NF-κB. While selective inhibition of BTK with ibrutinib causes clinical responses in relapsed DLBCL patients, most responses are partial and of a short duration. Here, we demonstrated that MyD88 silencing enhanced ibrutinib efficacy in DLBCL cells harboring MyD88 L265P mutations. Chemical downregulation of MyD88 expression with HDAC inhibitors also synergized with ibrutinib. We demonstrate that HDAC inhibitor regulation of MyD88 expression is mediated by STAT3. In turn, STAT3 silencing caused a decrease in MyD88 mRNA and protein levels, and enhanced the ibrutinib antilymphoma effect in MyD88 mutant DLBCL cells. Induced mutations in the STAT3 binding site in the MyD88 promotor region was associated with a decrease in MyD88 transcriptional activity. We also demonstrate that treatment with the HDAC inhibitor panobinostat decreased phosphorylated STAT3 binding to the MyD88 promotor. Accordingly, combined treatment with panobinostat and ibrutinib resulted in enhanced inhibition of NF-κB activity and caused regression of DLBCL xenografts. Our data provide a mechanistic rationale for combining HDAC inhibitors and ibrutinib for the treatment of DLBCL. PMID:28352655

  19. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma

    PubMed Central

    Micallef, Ivana N. M.; Maurer, Matthew J.; Wiseman, Gregory A.; Nikcevich, Daniel A.; Kurtin, Paul J.; Cannon, Michael W.; Perez, Domingo G.; Soori, Gamini S.; Link, Brian K.; Habermann, Thomas M.

    2011-01-01

    Approximately 60% of patients with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) are curable with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemoimmunotherapy. Epratuzumab (E) is an unlabeled anti-CD22 monoclonal antibody with efficacy in relapsed DLBCL. This phase 2 trial tested the safety and efficacy of combining E with R-CHOP (ER-CHOP) in untreated DLBCL. A secondary aim was to assess the efficacy of interim positron emission tomography (PET) to predict outcome in DLBCL. Standard R-CHOP with the addition of E 360 mg/m2 intravenously was administered for 6 cycles. A total of 107 patients were enrolled in the study. Toxicity was similar to standard R-CHOP. Overall response rate in the 81 eligible patients was 96% (74% CR/CRu) by computed tomography scan and 88% by PET. By intention to treat analysis, at a median follow-up of 43 months, the event-free survival (EFS) and overall survival (OS) at 3 years in all 107 patients were 70% and 80%, respectively. Interim PET was not associated with EFS or OS. Comparison with a cohort of 215 patients who were treated with R-CHOP showed an improved EFS in the ER-CHOP patients. ER-CHOP is well tolerated and results appear promising as a combination therapy. This study was registered at www.clinicaltrials.gov as #NCT00301821. PMID:21673350

  20. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma.

    PubMed

    Micallef, Ivana N M; Maurer, Matthew J; Wiseman, Gregory A; Nikcevich, Daniel A; Kurtin, Paul J; Cannon, Michael W; Perez, Domingo G; Soori, Gamini S; Link, Brian K; Habermann, Thomas M; Witzig, Thomas E

    2011-10-13

    Approximately 60% of patients with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) are curable with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemoimmunotherapy. Epratuzumab (E) is an unlabeled anti-CD22 monoclonal antibody with efficacy in relapsed DLBCL. This phase 2 trial tested the safety and efficacy of combining E with R-CHOP (ER-CHOP) in untreated DLBCL. A secondary aim was to assess the efficacy of interim positron emission tomography (PET) to predict outcome in DLBCL. Standard R-CHOP with the addition of E 360 mg/m(2) intravenously was administered for 6 cycles. A total of 107 patients were enrolled in the study. Toxicity was similar to standard R-CHOP. Overall response rate in the 81 eligible patients was 96% (74% CR/CRu) by computed tomography scan and 88% by PET. By intention to treat analysis, at a median follow-up of 43 months, the event-free survival (EFS) and overall survival (OS) at 3 years in all 107 patients were 70% and 80%, respectively. Interim PET was not associated with EFS or OS. Comparison with a cohort of 215 patients who were treated with R-CHOP showed an improved EFS in the ER-CHOP patients. ER-CHOP is well tolerated and results appear promising as a combination therapy. This study was registered at www.clinicaltrials.gov as #NCT00301821.

  1. [MGMT expression in primary central nervous system diffuse large B cell lymphoma and its relationship with prognosis].

    PubMed

    Shi, Q Y; Feng, X; Wang, J J; Wang, X; Bao, W; Ma, J; Shi, Q L

    2016-12-08

    Objective: To study the correlation between MGMT expression, clinicopathologic features and post-chemotherapy prognosis in patients with primary central nervous system lymphoma diffuse large B-cell lymphoma (PCNS-DLBCL). Methods: MGMT expression was detected in 76 cases of PCNS-DLBCL by EnVision method with immunohistochemical staining.Follow-up data including treatment response and overall survival time, were analyzed. Results: The rate of MGMT expression in PCNS-DLBCL was 67.1%(51/76). The MGMT expression rate in male patients was higher than that in female(P<0.05). Univariate analysis showed that these clinical pathological characteristics affected the overall survival of PCNS-DLBCL patients, including age and Hans algorithm, although no statistical significance was detected(P value was 0.065 and 0.069 respectively). The overall survival of the patients with positive MGMT and aged over 60 years was shorter after chemotherapy than those without chemotherapy (P=0.022). In the patients aged over 60 years, the prognosis of MGMT-positive patients was significantly better than MGMT-negative patients (P=0.044). Conclusions: The expression of MGMT is more commonly found in male patients. In the patients aged over 60 years with the same therapy, the prognosis is better in the MGMT-negative ones. Detection of MGMT protein expression can provide some guidance in choice of treatment modalities in PCNS-DLBCL patients.

  2. Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma

    PubMed Central

    Ezell, Scott A.; Wang, Suping; Bihani, Teeru; Lai, Zhongwu; Grosskurth, Shaun E.; Tepsuporn, Suprawee; Davies, Barry R.; Huszar, Dennis; Byth, Kate F.

    2016-01-01

    Agents that target components of the PI3K/AKT/mTOR pathway are under investigation for the treatment of diffuse large B cell lymphoma (DLBCL). Given the highly heterogeneous nature of DLBCL, it is not clear whether all subtypes of DLBCL will be susceptible to PI3K pathway inhibition, or which kinase within this pathway is the most favorable target. Pharmacological profiling of a panel of DLBCL cell lines revealed a subset of DLBCL that was resistant to AKT inhibition. Strikingly, sensitivity to AKT inhibitors correlated with the ability of these inhibitors to block phosphorylation of S6K1 and ribosomal protein S6. Cell lines resistant to AKT inhibition activated S6K1 independent of AKT either through upregulation of PIM2 or through activation by B cell receptor (BCR) signaling components. Finally, combined inhibition of AKT and BTK, PIM2, or S6K1 proved to be an effective strategy to overcome resistance to AKT inhibition in DLBCL. PMID:26824321

  3. Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses.

    PubMed

    Todorovic Balint, Milena; Jelicic, Jelena; Mihaljevic, Biljana; Kostic, Jelena; Stanic, Bojana; Balint, Bela; Pejanovic, Nadja; Lucic, Bojana; Tosic, Natasa; Marjanovic, Irena; Stojiljkovic, Maja; Karan-Djurasevic, Teodora; Perisic, Ognjen; Rakocevic, Goran; Popovic, Milos; Raicevic, Sava; Bila, Jelena; Antic, Darko; Andjelic, Bosko; Pavlovic, Sonja

    2016-05-06

    The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach.

  4. Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses

    PubMed Central

    Todorovic Balint, Milena; Jelicic, Jelena; Mihaljevic, Biljana; Kostic, Jelena; Stanic, Bojana; Balint, Bela; Pejanovic, Nadja; Lucic, Bojana; Tosic, Natasa; Marjanovic, Irena; Stojiljkovic, Maja; Karan-Djurasevic, Teodora; Perisic, Ognjen; Rakocevic, Goran; Popovic, Milos; Raicevic, Sava; Bila, Jelena; Antic, Darko; Andjelic, Bosko; Pavlovic, Sonja

    2016-01-01

    The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach. PMID:27164089

  5. Switching to BCL-6 Negativity in Relapsed Diffuse Large B Cell Lymphoma Correlated with More Aggressive Disease Course.

    PubMed

    Todorović, Milena; Balint, Bela; Andjelic, Bosko; Radisavljevic, Ziv; Mihaljevic, Biljana

    2014-12-01

    Diffuse large B-cell lymphoma (DLBCL) is the most frequent, complex and heterogeneous lymphoma of adulthood. Heterogeneity is expressed at clinical, genetic, and molecular levels. It is known that BCL-6 expression is a favorable prognostic factor in DLBCL. However, the underlying mechanisms of BCL-6 expression in DLBCL relapse are not yet elucidated. Here, we present so far undescribed clinical phenomenon of switching BCL-6(+) protein expression into BCL-6(-) expression in 19 of 41 relapsed DLBCL patients. The switch in relapsed DLBCL was associated with more aggressive clinical course of the disease. Bone marrow infiltration and high IPI risk were more often present in BCL-6(-) patients. Significantly increased biochemical parameters, such as LDH, beta-2 macroglobulin, CRP, and ferritin have been found, as well as significantly decreased serum Fe, TIBC, and hemoglobin. A Ki-67 proliferation marker was considerably high in relapsed DLBCL, but without significant differences between BCL-6(+) and BCL-6(-) groups of patients. Thus, switching of the positive into negative BCL-6 expression during DLBCL relapse could be used as a prognostic factor and a valuable criterion for treatment decision.

  6. Renal Infiltration by Diffuse Large B-Cell Lymphoma as a Rare Cause of Fanconi's Syndrome: A Case Report.

    PubMed

    Saadat, Shoab; Mahmud, Syed Nayer; Qureshi, Asim

    2016-11-30

    We report the case of a 16-year-old female patient with a known history of coeliac disease, who presented with the complaints of diarrhea, vomiting and generalized body weakness. On examination, she was found to have dehydration, decreased power in all her limbs, cervical lymphadenopathy and hepatosplenomegaly. Investigations showed severe hypokalemia, hyponatremia, hypomagnesemia, hypoglycemia and mildly enlarged kidneys on ultrasonography. Biopsy of the duodenum confirmed the flare up of coeliac disease, while cervical lymph node biopsy was positive for atypical lymphoid infiltrate and a morphology suggestive of non-Hodgkin's lymphoma. The immune profile performed on this sample confirmed the presence of activated/non-germinal center type of diffuse large B cell lymphoma (DLBCL), which was morphologically aggressive in type. The bone marrow biopsy was hypocellular and was negative for any infiltration. The patient was suspected to have developed infiltration of one or both kidneys leading to a rare presentation of Fanconi's syndrome. She was given first dose of rituximab on the 14th day of her admission. Unfortunately, she developed cardiopulmonary arrest and expired on the next day. We recommend screening for a possible renal involvement in patients with DLBCL and in patients with unusually deranged serum electrolytes as seen in Fanconi's syndrome. Renal biopsy is considered the gold standard modality for diagnosis and if possible, an earlier sample in a patient with newly developed acute kidney injury can save future complications.

  7. Primary Pulmonary Diffuse Large B Cell Non-Hodgkin’s Lymphoma: A Case Report and Literature Review

    PubMed Central

    Zhu, Ziqiang; Liu, Wei; Mamlouk, Omar; O’Donnell, James E.; Sen, Debabrata; Avezbakiyev, Boris

    2017-01-01

    Patient: Female, 48 Final Diagnosis: Primary pulmonary DLBCL Symptoms: Cough • weigh loss Medication: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) Clinical Procedure: Bone marrow biopsy • CT-guided lung biopsy Specialty: Oncology Objective: Rare disease Background: Primary pulmonary diffuse large B cell lymphoma (DLBCL) is extremely rare neoplasm representing only 0.5–1% of primary pulmonary malignancies. These patients usually have non-specific clinical presentation and radiological findings. Therefore, it is important to increase awareness of this rare disease, as the correct characterization of the tumors will have therapeutic and prognostic implications. Case Report: We present the case of a middle-aged Hispanic woman with chronic cough and an abnormal chest X-ray revealing a lung mass, who was found to have primary pulmonary DLBCL. She underwent 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy and attained complete remission. Conclusions: With its non-specific presentation, the diagnosis of primary pulmonary DLBCL is very challenging and often leads to misdiagnosis or delayed diagnosis. The pathogenesis of primary pulmonary DLBCL is still poorly understood. The choice of treatment approach should be based on the biological characteristic of the tumor, stage, and performance status. PMID:28321110

  8. Evaluation of the diffuse contamination of soils caused by residues coming from the large scale production of phosphate fertilisers

    NASA Astrophysics Data System (ADS)

    Martinez, M. J.; Perez-Sirvent, C.; Martinez-Lopez, S.; Bolivar, J. P.; Mosqueda, F.; Vaca, F.; Garcia-Tenorio, R.

    2012-04-01

    The obtaining of phosphate fertilizers results in large amounts of residues that are frequently accumulated in deposits or pools occupying a wide area. These residues are acidic, and contain variable amounts of trace elements and radionuclides. The potentially polluting agents can be leached by rainwater, and so transferred to the surface waters and then to the groundwater after soil infiltration. Since the distribution and thickness of the residue deposits are variable, the contaminants cannot be easily traced back to a single, well defined source, and so a diffuse contamination (nonpoint source pollution) of the surrounding soils and waters occurs. This communication reports the results obtained in the study of soils close to the phosphogypsum deposits placed near Rio Tinto (Huelva, Spain). The zone is affected not only by the mentioned residues but also by the tides due to the vicinity of the sea. The samples studied had a low organic content and a low acidity with average values of 30 mS/cm for the EC. The mineralogical study allowed illite, goethite, quartz, gypsum and kaolinite to be identified as the main mineralogical components. Although the arsenic level was relatively high (about 600 mg/Kg) the data proved that this element is not mobilized into water. Analytical data for 238U , 234U, 235U, 228Th, 230Th, 232Th, 226Ra, 228Ra, 210Po, 40K , 137Cs were also obtained.

  9. Primary bone diffuse large B-cell lymphoma: a retrospective evaluation on 76 cases from French institutional and LYSA studies.

    PubMed

    Pilorge, Sylvain; Harel, Stephanie; Ribrag, Vincent; Larousserie, Frédérique; Willems, Lise; Franchi, Patricia; Legoff, Marielle; Biau, David; Anract, Philippe; Roux, Christian; Blanc-Autran, Estelle; Delarue, Richard; Gisselbrecht, Christian; Ketterer, Nicolas; Recher, Christian; Bonnet, Christophe; Peyrade, Frederic; Haioun, Corinne; Tilly, Hervé; Salles, Gilles; Brice, Pauline; Bouscary, Didier; Deau, Bénédicte; Tamburini, Jerome

    2016-12-01

    Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare DLBCL location variant. We treated 76 PB-DLBCL patients by immuno-chemotherapy, resulting in an 84% sustained complete remission rate and a 78.9% survival over a 4.7-year median follow-up period. Ann Arbor stage IV and high age-adjusted international prognostic index were predictive of adverse outcome in univariate analysis. In multivariate analysis using a Cox model, only aa-IPI predicted long-term survival. While based on a limited number of cases, we suggested that radiotherapy may be useful as a consolidation modality in PB-DLBCL. We also suggested that positron emission tomography/CT scan should be interpreted with caution due to a persistent [18F]fluorodeoxyglucose [18FDG] uptake of bone lesions even after remission in some in PB-DLBCL patients. Our study based on a homogeneous cohort of PB-DLBCL patients confirmed the favorable outcome of this DLBCL variant and support the implementation of prospective clinical trials in this disease.

  10. Pineal Diffuse Large B-Cell Lymphoma Concomitant With Pituitary Prolactinoma: Possible Correlation Between 2 Distinguished Pathologies

    PubMed Central

    Kim, Yeong-Jin; Kim, Hee Kyung; Yang, Deok-Hwan; Jung, Shin; Noh, Myung-Giun; Lee, Jae-Hyuk; Lee, Kyung-Hwa; Moon, Kyung-Sub

    2016-01-01

    Abstract This is the first reported case of pineal lymphoma with concomitant prolactin-producing pituitary adenoma. A 51-year-old male experienced worsening headaches accompanied by nausea, diplopia, and memory loss for 1 month. Cranial nerve examination revealed bilateral upward gaze limitation with convergence impairment, which is known as Parinaud syndrome. Magnetic resonance images revealed a mass in the pineal gland with a coexisting mass within the enlarged sella fossa. Hormone analysis revealed hyperprolactinemia. The pineal mass was removed without injuring the hypothalamus, brain stem, or any neighboring vessels. Pathology examination confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL) involving the pineal gland. After further studies, the pineal lymphoma was determined to be a secondary tumor from a gastric primary tumor. The patient died 6 months after diagnosis due to systemic progression of DLBCL. Although the mechanistic link between hyperprolactinemia and lymphoma progression has not been clarified on a clinical basis, high prolactin levels may contribute to the rapid progression and therapeutic resistance of the lymphoma. PMID:26937937

  11. Extranodal involvement in young patients with diffuse large B-cell lymphoma: distribution, prognostic value and treatment options

    PubMed Central

    Yao, Shuna; Li, Junbo; Yao, Zhihua; Xu, Yuanlin; Chu, Junfeng; Zhang, Jiuyang; Jin, Shuiling; Huang, Yangyang; Zhang, Jianbo; Ma, Jie; Zhao, Yan; Yang, Shujun; Liu, Yanyan

    2017-01-01

    Objective Extranodal involvement represents a peculiar presentation of diffuse large B-cell lymphoma (DLBCL). Previous studies have suggested that older patients are more prone to extranodal involvement. This study retrospectively addressed the distribution, prognostic value and treatment options of extranodal involvement in young patients with DLBCL. Methods A total of 329 patients were enrolled according to the inclusion requirements. The effects of gender, extranodal involvement, age-adjusted international prognostic index (aaIPI), rituximab infusion and radiotherapy on patient outcomes were evaluated. Results Among these patients, 59% presented extranodal involvement in 16 anatomic sites. More than one instance was linked to many poorer clinical characteristics and poorer survival compared with either nodal disease or one instance. In patients with one extranodal lesion, multivariate analysis revealed that the site of extranodal involvement, but not the aaIPI or rituximab infusion, was independently related to the outcome, and radiotherapy had a negative influence on survival. Conclusions Extranodal involvement is common in younger patients and exhibits a ubiquitous distribution. The site of extranodal involvement is of strong prognostic significance. Radiotherapy for extranodal lesions does not improve patient outcomes. PMID:28373754

  12. Pineal Diffuse Large B-Cell Lymphoma Concomitant With Pituitary Prolactinoma: Possible Correlation Between 2 Distinguished Pathologies: A Case Report.

    PubMed

    Kim, Yeong-Jin; Kim, Hee Kyung; Yang, Deok-Hwan; Jung, Shin; Noh, Myung-Giun; Lee, Jae-Hyuk; Lee, Kyung-Hwa; Moon, Kyung-Sub

    2016-02-01

    This is the first reported case of pineal lymphoma with concomitant prolactin-producing pituitary adenoma.A 51-year-old male experienced worsening headaches accompanied by nausea, diplopia, and memory loss for 1 month. Cranial nerve examination revealed bilateral upward gaze limitation with convergence impairment, which is known as Parinaud syndrome. Magnetic resonance images revealed a mass in the pineal gland with a coexisting mass within the enlarged sella fossa. Hormone analysis revealed hyperprolactinemia. The pineal mass was removed without injuring the hypothalamus, brain stem, or any neighboring vessels. Pathology examination confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL) involving the pineal gland. After further studies, the pineal lymphoma was determined to be a secondary tumor from a gastric primary tumor. The patient died 6 months after diagnosis due to systemic progression of DLBCL.Although the mechanistic link between hyperprolactinemia and lymphoma progression has not been clarified on a clinical basis, high prolactin levels may contribute to the rapid progression and therapeutic resistance of the lymphoma.

  13. Two-Dimensional Matrix Algorithm Using Detrended Fluctuation Analysis to Distinguish Burkitt and Diffuse Large B-Cell Lymphoma

    PubMed Central

    Yeh, Rong-Guan; Lin, Chung-Wu; Abbod, Maysam F.; Shieh, Jiann-Shing

    2012-01-01

    A detrended fluctuation analysis (DFA) method is applied to image analysis. The 2-dimensional (2D) DFA algorithms is proposed for recharacterizing images of lymph sections. Due to Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), there is a significant different 5-year survival rates after multiagent chemotherapy. Therefore, distinguishing the difference between BL and DLBCL is very important. In this study, eighteen BL images were classified as group A, which have one to five cytogenetic changes. Ten BL images were classified as group B, which have more than five cytogenetic changes. Both groups A and B BLs are aggressive lymphomas, which grow very fast and require more intensive chemotherapy. Finally, ten DLBCL images were classified as group C. The short-term correlation exponent α1 values of DFA of groups A, B, and C were 0.370 ± 0.033, 0.382 ± 0.022, and 0.435 ± 0.053, respectively. It was found that α1 value of BL image was significantly lower (P < 0.05) than DLBCL. However, there is no difference between the groups A and B BLs. Hence, it can be concluded that α1 value based on DFA statistics concept can clearly distinguish BL and DLBCL image. PMID:23365623

  14. Composite diffuse large B-cell lymphoma and classical Hodgkin's lymphoma of the stomach: case report and literature review.

    PubMed

    Wang, Hong-Wei; Yang, Wen; Wang, Lin; Lu, Yun-Long; Lu, Jiang-Yang

    2013-10-07

    The combination of classical Hodgkin's lymphoma (cHL) and non-Hodgkin lymphoma coexisting in the same patient is not common, especially in one extranodal location. Here we present a rare case of composite diffuse large B-cell lymphoma (DLBCL) and cHL occurring simultaneously in the stomach of a 53-year-old female who presented with upper abdominal discomfort and gas pain. Surgery was performed and the disease was diagnosed pathologically as composite lymphoma of DLBCL and cHL using hematoxylin-eosin and immunohistochemical staining. Epstein-Barr virus (EBV) infection was not detected by in situ hybridization for EBV-encoded RNA or immunohistochemistry for EBV latent membrane protein-1. Polymerase chain reaction analysis from the two distinct components of the tumor demonstrated clonal immunoglobulin κ light chain gene rearrangements. The patient died approximately 11 mo after diagnosis in spite of receiving eight courses of the CHOP and two courses of the rituximab-CHOP (RCHOP) chemotherapy regimen. This case report showed that the two distinct components, DLBCL and cHL, appeared to originate from the same clonal progenitor cell, and that EBV infection was not essential for transformation during the course of tumorigenesis.

  15. Loss of RUNX3 expression is an independent adverse prognostic factor in diffuse large B-cell lymphoma.

    PubMed

    Duncan, Virginia E; Ping, Zheng; Varambally, Sooryanarayana; Peker, Deniz

    2017-01-01

    Runt-related transcription factor-3 (RUNX3) is an apoptotic factor correlated with tumorigenesis and cancer progression. Enhancer of zeste homolog-2 (EZH2), a histone methyltransferase, has been shown to mediate silencing of RUNX3. We investigated RUNX3 and EZH2 expression in diffuse large B-cell lymphoma (DLBCL). A chart review was conducted and tissue-microarray (TMA) was constructed using archived tissue from 83 DLBCL cases. RUNX3 and EZH2 protein expression was correlated with immunophenotypic subtypes and survival. Loss of RUNX3 was observed in 20 cases; EZH2 expression was observed in 59 cases. RUNX3-negative tumors had significantly lower overall and recurrence-free survival (log-rank test, p < 0.0001 for each). No correlation was found between RUNX3 and EZH2 staining (r = 0.14; p = 0.2). Results suggest a role for the RUNX3 gene in the pathogenesis of DLBCL. Loss of RUNX3 expression strongly correlated with adverse prognosis, independent of subtype. Further studies are warranted to elucidate the biology and prognostic utility of RUNX3 in DLBCL.

  16. Combinatorial BTK and MALT1 inhibition augments killing of CD79 mutant diffuse large B cell lymphoma.

    PubMed

    Nagel, Daniel; Bognar, Miriam; Eitelhuber, Andrea C; Kutzner, Kerstin; Vincendeau, Michelle; Krappmann, Daniel

    2015-12-08

    Survival of activated B cell-subtype (ABC) of diffuse large B cell lymphoma (DLBCL) is driven by chronic B cell receptor (BCR) signaling that activates the canonical NF-κB pathway. Inhibition of BTK by Ibrutinib has been shown to kill ABC DLBCL cells that carry activating mutations in the BCR adaptor CD79. However, mutations in BTK or in downstream components such as CARMA1/CARD11 can render lymphomas Ibrutinib resistant. Therefore, we assessed here the simultaneous inhibition of BTK and the protease MALT1 that acts downstream of CARMA1 and is essential for ABC DLBCL tumor growth. We show that in CD79 mutant cells BTK is a crucial upstream regulator of MALT1, but dispensable in CARMA1 mutant ABC DLBCL. Combined inhibition of BTK by Ibrutinib and MALT1 by S-Mepazine additively impaired MALT1 cleavage activity and expression of NF-κB pro-survival factors. Thereby, combinatorial Ibrutinib and S-Mepazine treatment enhanced killing of CD79 mutant ABC DLBCL cells. Moreover, while expression of oncogenic CARMA1 in CD79 mutant cells conferred Ibrutinib resistance, double mutant cells were still sensitive to MALT1 inhibition by S-Mepazine. Thus, based on the genetic background combinatorial BTK and MALT1 inhibition may improve effectiveness of therapeutic treatment and reduce the chances for the development of drug resistances.

  17. Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma.

    PubMed

    Hailfinger, Stephan; Lenz, Georg; Ngo, Vu; Posvitz-Fejfar, Anita; Rebeaud, Fabien; Guzzardi, Montserrat; Penas, Eva-Maria Murga; Dierlamm, Judith; Chan, Wing C; Staudt, Louis M; Thome, Margot

    2009-11-24

    A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is relevant for tumor growth. Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype. Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines. These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy.

  18. Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets.

    PubMed

    Norberg, Erik; Lako, Ana; Chen, Pei-Hsuan; Stanley, Illana A; Zhou, Feng; Ficarro, Scott B; Chapuy, Bjoern; Chen, Linfeng; Rodig, Scott; Shin, Donghyuk; Choi, Dong Wook; Lee, Sangho; Shipp, Margaret A; Marto, Jarrod A; Danial, Nika N

    2017-02-01

    Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR-DLBCLs, which is linked to greater protein abundance of ETC components. To gain insights into molecular determinants of the selective increase in ETC activity and dependence on mitochondrial energy metabolism in OxPhos-DLBCLs, we examined the mitochondrial translation pathway in charge of the synthesis of mitochondrial DNA encoded ETC subunits. Quantitative mass spectrometry identified increased expression of mitochondrial translation factors in OxPhos-DLBCL as compared with the BCR subtype. Biochemical and functional assays indicate that the mitochondrial translation pathway is required for increased ETC activity and mitochondrial energy reserves in OxPhos-DLBCL. Importantly, molecular depletion of several mitochondrial translation proteins using RNA interference or pharmacological perturbation of the mitochondrial translation pathway with the FDA-approved inhibitor tigecycline (Tigecyl) is selectively toxic to OxPhos-DLBCL cell lines and primary tumors. These findings provide additional molecular insights into the metabolic characteristics of OxPhos-DLBCLs, and mark the mitochondrial translation pathway as a potential therapeutic target in these tumors.

  19. Histological transformation to diffuse large B-cell lymphoma in patients with Waldenström macroglobulinemia.

    PubMed

    Castillo, Jorge J; Gustine, Joshua; Meid, Kirsten; Dubeau, Toni; Hunter, Zachary R; Treon, Steven P

    2016-10-01

    Histological transformation to diffuse large B-cell lymphoma (DLBCL) rarely occurs in patients with Waldenström Macroglobulinemia (WM). We identified 20 patients out of a cohort of 1,466 WM patients who experienced histologic transformation. The 5, 10, and 15-year cumulative incidence rates were 1, 2.4, and 3.8%, respectively. Approximately half of the patients were naive to nucleoside analogues, and a quarter were previously untreated for WM at the time of transformation. More than 80% of patients presented with extranodal involvement, 65% with high IPI scores. DLBCL cells did not express CD10 but expressed BCL6 and BCL2. All patients were treated with chemoimmunotherapy. The median survival from histological transformation was 2.7 years. The median overall survival was shorter for transformed patients versus those who did not transform (estimated 9 vs. 16 years; P = 0.09). Histological transformation to DLBCL is rare, and is associated with inferior survival in WM. Am. J. Hematol. 91:1032-1035, 2016. © 2016 Wiley Periodicals, Inc.

  20. T-cell defect in diffuse large B-cell lymphomas involves expansion of myeloid-derived suppressor cells.

    PubMed

    Azzaoui, Imane; Uhel, Fabrice; Rossille, Delphine; Pangault, Celine; Dulong, Joelle; Le Priol, Jerome; Lamy, Thierry; Houot, Roch; Le Gouill, Steven; Cartron, Guillaume; Godmer, Pascal; Bouabdallah, Krimo; Milpied, Noel; Damaj, Gandhi; Tarte, Karin; Fest, Thierry; Roussel, Mikael

    2016-08-25

    In diffuse large B-cell lymphoma (DLBCL), the number of circulating monocytes and neutrophils represents an independent prognostic factor. These cell subsets include monocytic and granulocytic myeloid-derived suppressor cells (M- and G-MDSCs) defined by their ability to suppress T-cell responses. MDSCs are a heterogeneous population described in inflammatory and infectious diseases and in numerous tumors including multiple myeloma, chronic lymphocytic leukemia, and DLBCL. However, their mechanisms of action remain unclear. We broadly assessed the presence and mechanisms of suppression of MDSC subsets in DLBCL. First, a myeloid suppressive signature was identified by gene expression profiling in DLBCL peripheral blood. Accordingly, we identified, in a cohort of 66 DLBCL patients, an increase in circulating G-MDSC (Lin(neg)HLA-DR(neg)CD33(pos)CD11b(pos)) and M-MDSC (CD14(pos)HLA-DR(low)) counts. Interestingly, only M-MDSC number was correlated with the International Prognostic Index, event-free survival, and number of circulating Tregs. Furthermore, T-cell proliferation was restored after monocyte depletion. Myeloid-dependent T-cell suppression was attributed to a release of interleukin-10 and S100A12 and increased PD-L1 expression. In summary, we identified expanded MDSC subsets in DLBCL, as well as new mechanisms of immunosuppression in DLBCL.

  1. Colonic diffuse large B-cell lymphoma in a liver transplant patient with historically very low tacrolimus levels.

    PubMed

    Moore, Christopher M; Lamzabi, Ihab; Bartels, Anne K; Jakate, Shriram; Van Thiel, David H

    2012-01-01

    Posttransplant lymphoproliferative disorders (PTLDs) comprise a wide spectrum of hematologic malignancies that are found increasingly in orthotopic liver transplant (OLT) patients given the rising frequency of these surgeries and their long-term success. PTLDs are highly correlated with both the Epstein-Barr virus (EBV) infection and the degree of immunosuppression involved. Herein is reported a case of a 53-year-old male with successfully treated hepatitis C virus genotype 4 and hepatocellular carcinoma who underwent OLT and developed symptoms of weakness and poor appetite 4 years later while on tacrolimus 3 mg b.i.d. with historically very low plasma levels. He was found to be anemic and colonoscopy revealed a 4.5 cm cecal diffuse large B-cell lymphoma (DLBCL). Further workup revealed mesenteric lymph node enlargement consistent and nodal DLBCL dissemination. He was treated with cyclophosphamide-hydroxyldaunorubicin-oncovin-prednisone-rituximab (CHOP-R) chemotherapy and his tacrolimus dose was lowered. Additionally, he manifested PTLD-associated cryoglobulinemia leading to acute kidney injury. After a prolonged hospitalization he was discharged with close followup.

  2. Prognostic role of pretreatment neutrophil-lymphocyte ratio in patients with diffuse large B-cell lymphoma treated with RCHOP

    PubMed Central

    Wang, Jing; Zhou, Min; Xu, Jing-Yan; Yang, Yong-Gong; Zhang, Qi-Guo; Zhou, Rong-Fu; Chen, Bing; Ouyang, Jian

    2016-01-01

    Abstract This study aims to investigate whether neutrophil to lymphocyte ratio (NLR) is an independent predictor in newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients in the rituximab era. Data from newly diagnosed DLBCL patients at Nanjing Drum Tower Hospital from 2006 to 2015 were retrospectively reviewed. We used the receiver operating characteristic (ROC) curve analysis to generate the optimal cutoff value for NLR. Among those 156 patients enrolled, the NLR was < 3.0 in 46.8% (73/156) of the patients, and the remaining 53.2% (83/156) had an NLR ≥ 3.0. Patients with higher pretreatment NLR were found to correlate with poorer OS and PFS than these with lower NLR (hazard ratio [HR] = 2.66, 95% confidence interval [CI] = 1.43–4.97, P = 0.002 and HR = 1.79, 95% CI = 1.05–3.07, P = 0.034, respectively). The multivariate Cox proportional hazard model analysis further showed that high NLR was found independently predictive of poor OS (HR = 0.40; CI = 0.19–0.84, P = 0.015) and PFS (HR = 0.57; CI = 0.33–0.98, P = 0.042). Consequently, pretreatment NLR was an independent prognostic predictor in patients with DLBCL in the rituximab era. PMID:27661033

  3. Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline.

    PubMed

    Pulvino, Mary; Chen, Luojing; Oleksyn, David; Li, Jing; Compitello, George; Rossi, Randy; Spence, Stephen; Balakrishnan, Vijaya; Jordan, Craig; Poligone, Brian; Casulo, Carla; Burack, Richard; Shapiro, Joel L; Bernstein, Steven; Friedberg, Jonathan W; Deshaies, Raymond J; Land, Hartmut; Zhao, Jiyong

    2015-06-20

    In searching for small-molecule compounds that inhibit proliferation and survival of diffuse large B-cell lymphoma (DLBCL) cells and may, therefore, be exploited as potential therapeutic agents for this disease, we identified the commonly used and well-tolerated antibiotic doxycycline as a strong candidate. Here, we demonstrate that doxycycline inhibits the growth of DLBCL cells both in vitro and in mouse xenograft models. In addition, we show that doxycycline accumulates in DLBCL cells to high concentrations and affects multiple signaling pathways that are crucial for lymphomagenesis. Our data reveal the deneddylating activity of COP-9 signalosome (CSN) as a novel target of doxycycline and suggest that doxycycline may exert its effects in DLBCL cells in part through a CSN5-HSP90 pathway. Consistently, knockdown of CSN5 exhibited similar effects as doxycycline treatment on DLBCL cell survival and HSP90 chaperone function. In addition to DLBCL cells, doxycycline inhibited growth of several other types of non-Hodgkin lymphoma cells in vitro. Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes.

  4. Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline

    PubMed Central

    Pulvino, Mary; Chen, Luojing; Oleksyn, David; Li, Jing; Compitello, George; Rossi, Randy; Spence, Stephen; Balakrishnan, Vijaya; Jordan, Craig; Poligone, Brian; Casulo, Carla; Burack, Richard; Shapiro, Joel L.; Bernstein, Steven; Friedberg, Jonathan W.; Deshaies, Raymond J.; Land, Hartmut; Zhao, Jiyong

    2015-01-01

    In searching for small-molecule compounds that inhibit proliferation and survival of diffuse large B-cell lymphoma (DLBCL) cells and may, therefore, be exploited as potential therapeutic agents for this disease, we identified the commonly used and well-tolerated antibiotic doxycycline as a strong candidate. Here, we demonstrate that doxycycline inhibits the growth of DLBCL cells both in vitro and in mouse xenograft models. In addition, we show that doxycycline accumulates in DLBCL cells to high concentrations and affects multiple signaling pathways that are crucial for lymphomagenesis. Our data reveal the deneddylating activity of COP-9 signalosome (CSN) as a novel target of doxycycline and suggest that doxycycline may exert its effects in DLBCL cells in part through a CSN5-HSP90 pathway. Consistently, knockdown of CSN5 exhibited similar effects as doxycycline treatment on DLBCL cell survival and HSP90 chaperone function. In addition to DLBCL cells, doxycycline inhibited growth of several other types of non-Hodgkin lymphoma cells in vitro. Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes. PMID:26142707

  5. The histological and biological spectrum of diffuse large B-cell lymphoma in the World Health Organization classification.

    PubMed

    Menon, Madhu P; Pittaluga, Stefania; Jaffe, Elaine S

    2012-01-01

    Diffuse large B-cell lymphomas (DLBCLs) are aggressive B-cell lymphomas that are clinically, pathologically, and genetically diverse, in part reflecting the functional diversity of the B-cell system. The focus in recent years has been toward incorporation of clinical features, morphology, immunohistochemistry, and ever evolving genetic data into the classification scheme. The 2008 World Health Organization classification reflects this complexity with the addition of several new entities and variants. The discovery of distinct subtypes by gene expression profiling heralded a new era with a focus on pathways of transformation as well as a promise of more targeted therapies, directed at specific pathways. Some DLBCLs exhibit unique clinical characteristics with a predilection for specific anatomic sites; the anatomic site often reflects underlying biological distinctions. Recently, the spectrum of Epstein-Barr virus (EBV)-driven B-cell proliferations in patients without iatrogenic or congenital immunosuppression has been better characterized; most of these occur in patients of advanced age and include Epstein-Barr virus (EBV)-positive large B-cell lymphoma of the elderly. Human herpesvirus 8 is involved in the pathogenesis of primary effusion lymphoma, which can present as a "solid variant." Two borderline categories were created; one deals with tumors at the interface between classic Hodgkin lymphoma and DLBCL. The second confronts the interface between Burkitt lymphoma and DLBCL, so-called "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma" in the 2008 classification. Most cases harbor both MYC and BCL2 translocations and are highly aggressive. Another interesting entity is anaplastic lymphoma kinase-positive DLBCL, which renders itself potentially targetable by anaplastic lymphoma kinase inhibitors. Ongoing investigations at the genomic level, with both exome and whole-genome sequencing, are sure to reveal new pathways

  6. Generation of large-scale, barrier-free diffuse plasmas in air at atmospheric pressure using array wire electrodes and nanosecond high-voltage pulses

    SciTech Connect

    Teng, Yun; Li, Lee Liu, Yun-Long; Liu, Lun; Liu, Minghai

    2014-10-15

    This paper introduces a method to generate large-scale diffuse plasmas by using a repetition nanosecond pulse generator and a parallel array wire-electrode configuration. We investigated barrier-free diffuse plasmas produced in the open air in parallel and cross-parallel array line-line electrode configurations. We found that, when the distance between the wire-electrode pair is small, the discharges were almost extinguished. Also, glow-like diffuse plasmas with little discharge weakening were obtained in an appropriate range of line-line distances and with a cathode-grounding cross-electrode configuration. As an example, we produced a large-scale, stable diffuse plasma with volumes as large as 18 × 15 × 15 cm{sup 3}, and this discharge region can be further expanded. Additionally, using optical and electrical measurements, we showed that the electron temperature was higher than the gas temperature, which was almost the same as room temperature. Also, an array of electrode configuration with more wire electrodes had helped to prevent the transition from diffuse discharge to arc discharge. Comparing the current waveforms of configurations with 1 cell and 9 cells, we found that adding cells significantly increased the conduction current and the electrical energy delivered in the electrode gaps.

  7. Analysis and experimental study on formation conditions of large-scale barrier-free diffuse atmospheric pressure air plasmas in repetitive pulse mode

    NASA Astrophysics Data System (ADS)

    Li, Lee; Liu, Lun; Liu, Yun-Long; Bin, Yu; Ge, Ya-Feng; Lin, Fo-Chang

    2014-01-01

    Atmospheric air diffuse plasmas have enormous application potential in various fields of science and technology. Without dielectric barrier, generating large-scale air diffuse plasmas is always a challenging issue. This paper discusses and analyses the formation mechanism of cold homogenous plasma. It is proposed that generating stable diffuse atmospheric plasmas in open air should meet the three conditions: high transient power with low average power, excitation in low average E-field with locally high E-field region, and multiple overlapping electron avalanches. Accordingly, an experimental configuration of generating large-scale barrier-free diffuse air plasmas is designed. Based on runaway electron theory, a low duty-ratio, high voltage repetitive nanosecond pulse generator is chosen as a discharge excitation source. Using the wire-electrodes with small curvature radius, the gaps with highly non-uniform E-field are structured. Experimental results show that the volume-scaleable, barrier-free, homogeneous air non-thermal plasmas have been obtained between the gap spacing with the copper-wire electrodes. The area of air cold plasmas has been up to hundreds of square centimeters. The proposed formation conditions of large-scale barrier-free diffuse air plasmas are proved to be reasonable and feasible.

  8. Generation of large-scale, barrier-free diffuse plasmas in air at atmospheric pressure using array wire electrodes and nanosecond high-voltage pulses

    NASA Astrophysics Data System (ADS)

    Teng, Yun; Li, Lee; Liu, Yun-Long; Liu, Lun; Liu, Minghai

    2014-10-01

    This paper introduces a method to generate large-scale diffuse plasmas by using a repetition nanosecond pulse generator and a parallel array wire-electrode configuration. We investigated barrier-free diffuse plasmas produced in the open air in parallel and cross-parallel array line-line electrode configurations. We found that, when the distance between the wire-electrode pair is small, the discharges were almost extinguished. Also, glow-like diffuse plasmas with little discharge weakening were obtained in an appropriate range of line-line distances and with a cathode-grounding cross-electrode configuration. As an example, we produced a large-scale, stable diffuse plasma with volumes as large as 18 × 15 × 15 cm3, and this discharge region can be further expanded. Additionally, using optical and electrical measurements, we showed that the electron temperature was higher than the gas temperature, which was almost the same as room temperature. Also, an array of electrode configuration with more wire electrodes had helped to prevent the transition from diffuse discharge to arc discharge. Comparing the current waveforms of configurations with 1 cell and 9 cells, we found that adding cells significantly increased the conduction current and the electrical energy delivered in the electrode gaps.

  9. Analysis and experimental study on formation conditions of large-scale barrier-free diffuse atmospheric pressure air plasmas in repetitive pulse mode

    SciTech Connect

    Li, Lee Liu, Lun; Liu, Yun-Long; Bin, Yu; Ge, Ya-Feng; Lin, Fo-Chang

    2014-01-14

    Atmospheric air diffuse plasmas have enormous application potential in various fields of science and technology. Without dielectric barrier, generating large-scale air diffuse plasmas is always a challenging issue. This paper discusses and analyses the formation mechanism of cold homogenous plasma. It is proposed that generating stable diffuse atmospheric plasmas in open air should meet the three conditions: high transient power with low average power, excitation in low average E-field with locally high E-field region, and multiple overlapping electron avalanches. Accordingly, an experimental configuration of generating large-scale barrier-free diffuse air plasmas is designed. Based on runaway electron theory, a low duty-ratio, high voltage repetitive nanosecond pulse generator is chosen as a discharge excitation source. Using the wire-electrodes with small curvature radius, the gaps with highly non-uniform E-field are structured. Experimental results show that the volume-scaleable, barrier-free, homogeneous air non-thermal plasmas have been obtained between the gap spacing with the copper-wire electrodes. The area of air cold plasmas has been up to hundreds of square centimeters. The proposed formation conditions of large-scale barrier-free diffuse air plasmas are proved to be reasonable and feasible.

  10. An Integrated Intervention for Increasing Clinical Nurses' Knowledge of HIV/AIDS-Related Occupational Safety.

    PubMed

    He, Liping; Lu, Zhiyan; Huang, Jing; Zhou, Yiping; Huang, Jian; Bi, Yongyi; Li, Jun

    2016-11-07

    Background: Approximately 35 new HIV (Human Immunodeficiency Virus, HIV) cases and at least 1000 serious infections are transmitted annually to health care workers. In China, HIV prevalence is increasing and nursing personnel are encountering these individuals more than in the past. Contaminated needle-stick injuries represent a significant occupational burden for nurses. Evidence suggests that nurses in China may not fully understand HIV/AIDS (Acquired immunodeficiency syndrome, AIDS) and HIV-related occupational safety. At this time, universal protection precautions are not strictly implemented in Chinese hospitals. Lack of training may place nurses at risk for occupational exposure to blood-borne pathogens. Objectives: To assess the effectiveness of integrated interventions on nurses' knowledge improvement about reducing the risk of occupationally acquired HIV infection. Methods: We audited integrated interventions using 300 questionnaires collected from nurses at the Affiliated Hospital of Xiangnan University, a public polyclinic in Hunan Province. The intervention studied was multifaceted and included appropriate and targeted training content for hospital, department and individual levels. After three months of occupational safety integrated interventions, 234 participants who completed the program were assessed. Results: Of the subjects studied, 94.3% (283/300) were injured one or more times by medical sharp instruments or splashed by body fluids in the last year and 95.3% considered their risk of occupational exposure high or very high. After the intervention, awareness of HIV/AIDS-related knowledge improved significantly (χ² = 86.34, p = 0.00), and correct answers increased from 67.9% to 82.34%. Correct answers regarding risk perception were significantly different between pre-test (54.4%) and post-test (66.6%) (χ² = 73.2, p = 0.00). When coming into contact with patient body fluids and blood only 24.0% of subjects used gloves regularly. The pre

  11. Study on effectiveness of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory AIDS-related non-Hodgkin's lymphoma.

    PubMed

    Zhong, Dong Ta; Shi, Chun Mei; Chen, Qiang; Huang, Jing Ze; Liang, Jian Gang

    2012-11-01

    Non-Hodgkin's lymphoma (NHL) remains the second most common malignant complication in patients with human immunodeficiency virus (HIV) infection. Even though NHL is commonly chemosensitive to primary treatment, failure or relapse still occurs in a large number of patients. We conducted this retrospective study to evaluate the efficacy and safety of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory AIDS-related NHL (AIDS-NHL). Forty-eight patients with relapsed or refractory AIDS-NHL were treated with intravenous combination chemotherapy with GDP. The overall objective response rate was 54.1% (95% confidence interval, CI, 40.1-68.3%), with 10 complete responses and 16 partial responses. The 2-year overall survival rate (OS) was 70.8% (95% CI 58.0-83.7%), and the 5-year OS was 41.7% (95% CI 27.7-55.6%). The 2-year progression-free survival rate (PFS) was 37.5% (95% CI 23.8-51.2%), and the 5-year PFS was 25.0% (95% CI 12.8-37.3%). The median progression-free survival was 8.8 months (95% CI 0-20.3 months), and the median overall survival was 40.6 months (95% CI 22.6-58.6 months). Patients with B cell tumors who relapsed but had no B symptoms were clinical stage I/II, had infiltration fewer than two extranodal sites, had CD4⁺ counts >200 cells/μL, and had lactate dehydrogenase (LDH) less than the upper limit of normal benefited from GDP. The level of LDH had a significant impact on the response rate to chemotherapy with GDP (P = 0.015). Myelosuppression was the main side effect; the incidence of grade 3-4 anemia was 8.3%; leukopenia, 37.5%; and thrombocytopenia, 48.3%. Univariate and multivariate analyses were performed to determine variables for OS and PFS. This study confirms that GDP is an effective and safe salvage regimen in relapsed or refractory AIDS-NHL, was associated with modest declines in CD4⁺ lymphocyte counts, and did not promote HIV-1 viral replication.

  12. Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: characteristics, outcomes, and prognostication among a large multicenter cohort.

    PubMed

    Evens, Andrew M; Kanakry, Jennifer A; Sehn, Laurie H; Kritharis, Athena; Feldman, Tatyana; Kroll, Aimee; Gascoyne, Randy D; Abramson, Jeremy S; Petrich, Adam M; Hernandez-Ilizaliturri, Francisco J; Al-Mansour, Zeina; Adeimy, Camille; Hemminger, Jessica; Bartlett, Nancy L; Mato, Anthony; Caimi, Paolo F; Advani, Ranjana H; Klein, Andreas K; Nabhan, Chadi; Smith, Sonali M; Fabregas, Jesus C; Lossos, Izidore S; Press, Oliver W; Fenske, Timothy S; Friedberg, Jonathan W; Vose, Julie M; Blum, Kristie A

    2015-09-01

    Gray zone lymphoma (GZL) with features between classical Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) is a recently recognized entity reported to present primarily with mediastinal disease (MGZL). We examined detailed clinical features, outcomes, and prognostic factors among 112 GZL patients recently treated across 19 North American centers. Forty-three percent of patients presented with MGZL, whereas 57% had non-MGZL (NMGZL). NMGZL patients were older (50 versus 37 years, P = 0.0001); more often had bone marrow involvement (19% versus 0%, P = 0.001); >1 extranodal site (27% versus 8%, P = 0.014); and advanced stage disease (81% versus 13%, P = 0.0001); but they had less bulk (8% versus 44%, P = 0.0001), compared with MGZL patients. Common frontline treatments were cyclophosphamide-doxorubicin-vincristine-prednisone +/- rituximab (CHOP+/-R) 46%, doxorubicin-bleomycin-vinblastine-dacarbazine +/- rituximab (ABVD+/-R) 30%, and dose-adjusted etoposide-doxorubicin-cyclophosphamide-vincristine-prednisone-rituximab (DA-EPOCH-R) 10%. Overall and complete response rates for all patients were 71% and 59%, respectively; 33% had primary refractory disease. At 31-month median follow-up, 2-year progression-free survival (PFS) and overall survival rates were 40% and 88%, respectively. Interestingly, outcomes in MGZL patients seemed similar compared with that of NMGZL patients. On multivariable analyses, performance status and stage were highly prognostic for survival for all patients. Additionally, patients treated with ABVD+/-R had markedly inferior 2-year PFS (22% versus 52%, P = 0.03) compared with DLBCL-directed therapy (CHOP+/-R and DA-EPOCH-R), which persisted on Cox regression (hazard ratio, 1.88; 95% confidence interval, 1.03-3.83; P = 0.04). Furthermore, rituximab was associated with improved PFS on multivariable analyses (hazard ratio, 0.35; 95% confidence interval, 0.18-0.69; P = 0.002). Collectively, GZL is a heterogeneous

  13. Immunohistochemical and genomic profiles of diffuse large B-cell lymphomas: Implications for targeted EZH2 inhibitor therapy?

    PubMed Central

    Dubois, Sydney; Mareschal, Sylvain; Picquenot, Jean-Michel; Viailly, Pierre-Julien; Bohers, Elodie; Cornic, Marie; Bertrand, Philippe; Veresezan, Elena Liana; Ruminy, Philippe; Maingonnat, Catherine; Marchand, Vinciane; Lanic, Hélène; Penther, Dominique; Bastard, Christian; Tilly, Hervé; Jardin, Fabrice

    2015-01-01

    Enhancer of Zeste Homolog 2 (EZH2) plays an essential epigenetic role in Diffuse Large B Cell Lymphoma (DLBCL) development. Recurrent somatic heterozygous gain-of-function mutations of EZH2 have been identified in DLBCL, most notably affecting tyrosine 641 (Y641), inducing hyper-trimethylation of H3K27 (H3K27me3). Novel EZH2 inhibitors are being tested in phase 1 and 2 clinical trials but no study has examined which patients would most benefit from this treatment. We evaluated the immunohistochemical (IHC) methylation profiles of 82 patients with DLBCL, as well as the mutational profiles of 32 patients with DLBCL using NGS analysis of a panel of 34 genes involved in lymphomagenesis. A novel IHC score based on H3K27me2 and H3K27me3 expression was developed, capable of distinguishing patients with wild-type (WT) EZH2 and patients with EZH2 Y641 mutations (p = 10−5). NGS analysis revealed a subclonal EZH2 mutation pattern in EZH2 mutant patients with WT-like IHC methylation profiles, while associated mutations capable of upregulating EZH2 were detected in WT EZH2 patients with mutant-like IHC methylation profiles. IHC and mutational profiles highlight in vivo hyper-H3K27me3 and hypo-H3K27me2 status, pinpoint associated activating mutations and determine EZH2 mutation clonality, maximizing EZH2 inhibitor potential by identifying patients most likely to benefit from treatment. PMID:25762637

  14. Sarcopenia is an independent prognostic factor in elderly patients with diffuse large B-cell lymphoma treated with immunochemotherapy.

    PubMed

    Lanic, Hélène; Kraut-Tauzia, Jerôme; Modzelewski, Romain; Clatot, Florian; Mareschal, Sylvain; Picquenot, Jean Michel; Stamatoullas, Aspasia; Leprêtre, Stéphane; Tilly, Hervé; Jardin, Fabrice

    2014-04-01

    Approximately 25-35% of patients with diffuse large B-cell lymphoma (DLBCL) are older than 70 years. The aim of this study was to investigate the prognostic impact of depletion of skeletal muscle (sarcopenia) in elderly patients with DLBCL. This retrospective analysis included 82 patients with DLBCL older than 70 years and treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin, prednisone) or R-miniCHOP. Sarcopenia was measured by the analysis of stored computed tomography (CT) images at the L3 level at baseline. The surface of the muscular tissues was selected according to the CT Hounsfield unit. This value was normalized for stature in order to calculate the lumbar L3 skeletal muscle index (LSMI, in cm(2)/m(2)). The mean age of the population was 78 years. According to the defined cut-offs for LSMI, 45 patients with DLBCL were considered sarcopenic. Sarcopenic patients displayed a higher revised International Prognostic Index (R-IPI) compared with patients without sarcopenia, and were older, with a mean age of 80 years and 77 years, respectively (p = 0.006). With a median follow-up of 39 months, the 2-year overall survival in the sarcopenic population was 46% compared with 84% in the non-sarcopenic group (HR = 3.22; 95% CI = 1.73-5.98; p = 0.0002). In a multivariate analysis, sarcopenia remained predictive of outcome (p = 0.005). Sarcopenia is a relevant and predictive factor in elderly patients with DLBCL treated with rituximab plus chemotherapy.

  15. RelA NF-κB subunit activation as a therapeutic target in diffuse large B-cell lymphoma

    PubMed Central

    Manyam, Ganiraju C.; Visco, Carlo; Tzankov, Alexandar; Wang, Jing; Montes-Moreno, Santiago; Dybkaer, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L.; Hsi, Eric D.; Choi, William W.L.; Han van Krieken, J.; Huh, Jooryung; Ponzoni, Maurilio; Ferreri, Andrés J.M.; Møller, Michael B.; Parsons, Ben M.; Winter, Jane N.; Piris, Miguel A.; Jeffrey Medeiros, L.; Pham, Lan V.; Young, Ken H.

    2016-01-01

    It has been well established that nuclear factor kappa-B (NF-κB) activation is important for tumor cell growth and survival. RelA/p65 and p50 are the most common NF-κB subunits and involved in the classical NF-κB pathway. However, the prognostic and biological significance of RelA/p65 is equivocal in the field. In this study, we assessed RelA/p65 nuclear expression by immunohistochemistry in 487 patients with de novo diffuse large B-cell lymphoma (DLBCL), and studied the effects of molecular and pharmacological inhibition of NF-κB on cell viability. We found RelA/p65 nuclear expression, without associations with other apparent genetic or phenotypic abnormalities, had unfavorable prognostic impact in patients with stage I/II DLBCL. Gene expressionprofiling analysis suggested immune dysregulation and antiapoptosis may be relevant for the poorer prognosis associated with p65 hyperactivation in germinal center B-cell–like (GCB) DLBCL and in activated B-cell–like (ABC) DLBCL, respectively. We knocked down individual NF-κB subunits in representative DLBCL cells in vitro, and found targeting p65 was more effective than targeting other NF-κB subunits in inhibiting cell growth and survival. In summary, RelA/p65 nuclear overexpression correlates with significant poor survival in early-stage DLBCL patients, and therapeutic targeting RelA/p65 is effective in inhibiting proliferation and survival of DLBCL with NF-κB hyperactivation. PMID:27941215

  16. DNA methyltransferase DNMT3b protein overexpression as a prognostic factor in patients with diffuse large B-cell lymphomas.

    PubMed

    Amara, Khaled; Ziadi, Sonia; Hachana, Mohamed; Soltani, Nabil; Korbi, Sadok; Trimeche, Mounir

    2010-07-01

    Diffuse large B-cell lymphomas (DLBCL) are the most common type of aggressive lymphomas, with considerable heterogeneity in clinical presentation, molecular characteristics, and outcome. Previous studies have showed significant correlations between DNA methyltransferase (DNMT) overexpression and unfavorable prognosis in human cancers. Therefore, we investigated in this study the biological and prognostic significance of DNMT1, DNMT3a, and DNMT3b protein expression in DLBCL. DNA methyltransferase (DNMT) expression was analyzed by immunohistochemistry in 81 DLBCL cases and correlated with clinicopathological parameters. Kaplan-Meier curves were used to estimate survival rates, and the Cox proportional hazard regression model was used to evaluate the prognostic impact of DNMT expression. Our results showed that overexpression of DNMT1, DNMT3a, and DNMT3b were detected in 48%, 13%, and 45% of investigated cases, respectively. DNA methyltransferase 1 (DNMT1) and DNMT3b overexpression was significantly correlated with advanced clinical stages (P = 0.028 and P = 0.016, respectively). Moreover, concomitant expression of DNMT1 and DNMT3b was significantly correlated with resistance to treatment (P = 0.015). With regard to survival rates, although data was available only for 40 patients, DNMT3b overexpression was significantly correlated with shorter overall survival (P = 0.006) and progression-free survival (P = 0.016). Interestingly, multivariate analysis demonstrated that DNMT3b overexpression was an independent prognostic factor for predicting shortened overall survival (P = 0.004) and progression-free survival (P = 0.024). In conclusion, DNMT3b overexpression was identified as an independent prognostic factor for predicting shortened survival of patients with DLBCL and could be, therefore, useful in identifying patients who would benefit from aggressive therapy.

  17. Array-comparative genomic hybridization profiling of immunohistochemical subgroups of diffuse large B-cell lymphoma shows distinct genomic alterations

    PubMed Central

    Guo, Ying; Takeuchi, Ichiro; Karnan, Sivasundaram; Miyata, Tomoko; Ohshima, Koichi; Seto, Masao

    2014-01-01

    Diffuse large B-cell lymphoma (DLBCL) displays striking heterogeneity at the clinical, genetic and molecular levels. Subtypes include germinal center B-cell-like (GCB) DLBCL and activated B-cell-like (ABC) DLBCL, according to microarray analysis, and germinal center type or non-germinal center type by immunohistochemistry. Although some reports have described genomic aberrations based upon microarray classification system, genomic aberrations based upon immunohistochemical classifications have rarely been reported. The present study aimed to ascertain the relationship between genomic aberrations and subtypes identified by immunohistochemistry, and to study the pathogenetic character of Chinese DLBCL. We conducted immunohistochemistry using antibodies against CD10, BCL6 and MUM1 in 59 samples of DLBCL from Chinese patients, and then performed microarray-based comparative genomic hybridization for each case. Characteristic genomic differences were found between GCB and non-GCB DLBCL from the array data. The GCB type was characterized by more gains at 7q (7q22.1, P < 0.05) and losses at 16q (P ≤ 0.05), while the non-GCB type was characterized by gains at 11q24.3 and 3q13.2 (P < 0.05). We found completely different mutations in BCL6+ and BCL6− non-GCB type DLBCL, whereby the BCL6− group had a higher number of gains at 1q and a loss at 14q32.13 (P ≤ 0.005), while the BCL6+ group showed a higher number of gains at 14q23.1 (P = 0.15) and losses at 6q (P = 0.07). The BCL6− group had a higher frequency of genomic imbalances compared to the BCL6+ group. In conclusion, the BCL6+ and BCL6− non-GCB type of DLBCL appear to have different mechanisms of pathogenesis. PMID:24843885

  18. Machine learning-based classification of diffuse large B-cell lymphoma patients by eight gene expression profiles.

    PubMed

    Zhao, Shuangtao; Dong, Xiaoli; Shen, Wenzhi; Ye, Zhen; Xiang, Rong

    2016-05-01

    Gene expression profiling (GEP) had divided the diffuse large B-cell lymphoma (DLBCL) into molecular subgroups: germinal center B-cell like (GCB), activated B-cell like (ABC), and unclassified (UC) subtype. However, this classification with prognostic significance was not applied into clinical practice since there were more than 1000 genes to detect and interpreting was difficult. To classify cancer samples validly, eight significant genes (MYBL1, LMO2, BCL6, MME, IRF4, NFKBIZ, PDE4B, and SLA) were selected in 414 patients treated with CHOP/R-CHOP chemotherapy from Gene Expression Omnibus (GEO) data sets. Cutoffs for each gene were obtained using receiver-operating characteristic curves (ROC) new model based on the support vector machine (SVM) estimated the probability of membership into one of two subgroups: GCB and Non-GCB (ABC and UC). Furtherly, multivariate analysis validated the model in another two cohorts including 855 cases in all. As a result, patients in the training and validated cohorts were stratified into two subgroups with 94.0%, 91.0%, and 94.4% concordance with GEP, respectively. Patients with Non-GCB subtype had significantly poorer outcomes than that with GCB subtype, which agreed with the prognostic power of GEP classification. Moreover, the similar prognosis received in the low (0-2) and high (3-5) IPI scores group demonstrated that the new model was independent of IPI as well as GEP method. In conclusion, our new model could stratify DLBCL patients with CHOP/R-CHOP regimen matching GEP subtypes effectively.

  19. CD38 and interleukin 6 gene polymorphism in egyptians with diffuse large B-cell lymphoma (DLBCL).

    PubMed

    Talaat, Roba M; Abdel-Aziz, Amal M; El-Maadawy, Eman A; Abdel-Bary, Naser

    2015-01-01

    Given the importance of understanding the genetic variations involved in the pathogenesis of non-Hodgkin's lymphoma (NHL), this pilot study was designed to investigate the impact of CD38 (184C/G; rs6449182) and IL-6 (-174 G/C; rs1800795) gene polymorphism on susceptibility of Egyptians to diffuse large B cell lymphoma (DLBCL); major types of NHL. To the best of our knowledge, this study is the first one that examines CD38 polymorphism in the NHL. Genotyping polymorphism is performed using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) for CD38 and Mutagenically separated PCR (MS-PCR) for IL-6 in 100 Egyptian NHL patients with DLBCL subtype and 119 normal controls. The serum level of IL-6 was measured using Enzyme-linked immunosorbent assay (ELISA). CD38 (184C/G) genotype is significantly increased in NHL patients (p < 0.01), while the GG genotype is significantly increased in controls (p < 0.05). Only two genotypes were found (GG and GC) in IL-6 (-174), no CC in our NHL patients and only one case in the controls. Insignificant change in IL-6 (-174 G/C) genotypes was recorded. Significantly increased serum IL-6 (p < 0.05) was positively correlated (r = 0.17; p < 0.05) with the disease. Taken together, our data stressed the importance of CD38 gene polymorphism in developing DLBCL. Our pilot study indicates that CD38 (184) CG genotype might play a role in DLBCL susceptibility in Egyptians. Additional prospective studies on larger population are needed to confirm our findings.

  20. Crystal Structures of Proto-oncogene Kinase Pim1: A Target of Aberrant Somatic Hypermutations in Diffuse Large Cell Lymphoma

    SciTech Connect

    Kumar, Abhinav; Mandiyan, Valsan; Suzuki, Yoshihisa; Zhang, Chao; Rice, Julie; Tsai, James; Artis, Dean R.; Ibrahim, Prabha; Bremer, Ryan

    2010-07-19

    Pim1, a serine/threonine kinase, is involved in several biological functions including cell survival, proliferation, and differentiation. While pim1 has been shown to be involved in several hematopoietic cancers, it was also recently identified as a target of aberrant somatic hypermutation in diffuse large cell lymphoma (DLCL), the most common form of non-Hodgkin's lymphoma. The crystal structures of Pim1 in apo form and bound with AMPPNP have been solved and several unique features of Pim1 were identified, including the presence of an extra {beta}-hairpin in the N-terminal lobe and an unusual conformation of the hinge connecting the two lobes of the enzyme. While the apo Pim1 structure is nearly identical with that reported recently, the structure of AMPPNP bound to Pim1 is significantly different. Pim1 is unique among protein kinases due to the presence of a proline residue at position 123 that precludes the formation of the canonical second hydrogen bond between the hinge backbone and the adenine moiety of ATP. One crystal structure reported here shows that changing P123 to methionine, a common residue that offers the backbone hydrogen bond to ATP, does not restore the ATP binding pocket of Pim1 to that of a typical kinase. These unique structural features in Pim1 result in novel binding modes of AMP and a known kinase inhibitor scaffold, as shown by co-crystallography. In addition, the kinase activities of five Pim1 mutants identified in DLCL patients have been determined. In each case, the observed effects on kinase activity are consistent with the predicted consequences of the mutation on the Pim1 structure. Finally, 70 co-crystal structures of low molecular mass, low-affinity compounds with Pim1 have been solved in order to identify novel chemical classes as potential Pim1 inhibitors. Based on the structural information, opportunities for optimization of one specific example are discussed.

  1. Prognostic significance of serum beta-2 microglobulin in patients with diffuse large B-cell lymphoma in the rituximab era

    PubMed Central

    Yoon, Shinkyo; Yoo, Changhoon; Park, Ji Hyun; Lee, Jung Bok; Park, Chan-sik; Huh, Jooryung; Lee, Yoonse; Kim, Kyung Won; Ryu, Jin-Sook; Kim, Seok Jin; Kim, Won Seog; Yoon, Dok Hyun; Suh, Cheolwon

    2016-01-01

    The prognostic value of serum beta-2 microglobulin for diffuse large B-cell lymphoma (DLBCL) is not well known in the rituximab era. A retrospective registry data analysis of 833 patients with de novo DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was conducted to establish the prognostic significance of serum beta-2 microglobulin at a ≥2.5 mg/L cutoff. Five-year progression-free survival (PFS, 76.1% vs. 41.0%; p < 0.001) and overall survival (OS, 83.8% vs. 49.2%; p < 0.001) were significantly worse in patients with elevated serum beta-2 microglobulin (n = 290, 34.8%). Furthermore, the five parameters of the International Prognostic Index, accompanying B symptoms, bone marrow involvement and impaired renal function were associated with worse PFS and OS. In multivariate analysis, elevated beta-2 microglobulin was a significant poor prognostic factor for PFS (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.29–2.24; p < 0.001) and OS (HR, 2.0; 95% CI, 1.47–2.75; p < 0.001). In an independent validation cohort of 258 R-CHOP treated patients with de novo DLBCL, elevated beta-2 microglobulin levels remained a significant poor prognostic factor for PFS (HR, 2.03; 95% CI, 1.23–3.32; p = 0.005) and exhibited a strong trend of association with worse OS (HR, 1.64; 95% CI, 0.98–2.75; p = 0.062). The significance of serum beta-2 microglobulin levels as an independent prognostic factor for patients with DLBCL receiving R-CHOP is confirmed. PMID:27764777

  2. EBV-positive diffuse large B-cell lymphoma of the elderly: a case series from Peru.

    PubMed

    Beltran, Brady E; Castillo, Jorge J; Morales, Domingo; de Mendoza, Fernando Hurtado; Quinones, Pilar; Miranda, Roberto N; Gallo, Aly; Lopez-Ilasaca, Marco; Butera, James N; Sotomayor, Eduardo M

    2011-08-01

    EBV-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is an entity recently included in the WHO classification of lymphoid tumors. We have reviewed our experience and clinical outcomes of this distinct subtype of DLBCL. Between 2002 and 2009, cases of DLBCL were identified from medical records of the Hospital Nacional Edgardo Rebagliati Martins in Lima, Peru, and underwent pathological evaluation including immunohistochemistry for CD20, CD10, bcl-6, MUM1/IRF4, and EBV-encoded RNA in situ hybridization. Clinical data were gathered, tabulated, and reported descriptively. Survival analyses were performed using Kaplan-Meier estimates. Out of 199 cases of DLBCL, 28 cases of EBV-positive DLBCL of the elderly were identified. The median age was 75 years with male predominance (1.5:1). B-symptoms were present in 43%, advanced stage in 50% and International Prognostic Index (IPI) score > 2 in 57% of patients; 68% of patients had a nongerminal center (NGC) phenotype. The complete response rates to R-CHOP and CHOP were 63% and 33%, respectively. The median overall survival (OS) for the group was 5 months. In the univariate analysis, age ≥70 years, lymphocyte count <1.0 × 10(9) /L, and advanced clinical stage were associated with worse OS in patients treated with chemotherapy with and without rituximab. EBV-positive DLBCL of the elderly is a clinically aggressive entity with a short OS and typically presents with advanced stage, high IPI score, and a NGC phenotype. Further studies are needed to investigate if rituximab-containing regimens are associated with better response and OS rates in EBV-positive DLBCL of the elderly.

  3. Epstein-Barr virus-positive diffuse large B-cell lymphoma association is not only restricted to elderly patients.

    PubMed

    Cohen, M; Narbaitz, M; Metrebian, F; De Matteo, E; Preciado, M V; Chabay, P A

    2014-12-15

    Diffuse large B-cell lymphoma (DLBCL), the most common group of malignant lymphomas, account for 30% of adult non-Hodgkin lymphomas. The 2008 World Health Organization (WHO) classification included a new entity, Epstein-Barr virus (EBV)+ DLBCL of the elderly, affecting patients aged 50 years or older. However, some reports of younger EBV+ DLBCL cases, without evidence of underlying immunosuppression, can be found. The role of EBV in tumor microenvironment composition in DLBCL is still not well understood. Our aim was to assess EBV presence and latency pattern as well as tumor T-cell population in an adult DLBCL series of Argentina. The study was conducted on biopsies from 75 DLBCL patients. EBERs expression was performed by in situ hybridization, while EBV gene expression was analyzed using real-time polymerase chain reaction. LMP1, LMP2A, EBNA2, EBNA3A, CD4, CD8 and Foxp3 expression was assessed by immunohistochemistry. Nine percent of cases showed EBV expression, with similar frequency among patients younger than 50 years and 50 years or older (13% and 8%, respectively). T-cell subsets were not altered by EBV presence. Latency type II was the most frequently observed, together with lytic gene expression in EBV+ DLBCL, with ≥20% of EBERs+ cells. These findings suggest that EBV+ DLBCL in our series was similar to the previously described in Asia and Latin-America, displaying latency II or III expression profile and no age-specific characteristics. Finally, EBV+ DLBCL may be an entity that is not only restricted to patients who are older than 50 years of age, in consequence the age cutoff revision may be a current goal.

  4. Polymorphisms in cytokine genes as prognostic markers in diffuse large B cell lymphoma patients treated with (R)-CHOP.

    PubMed

    Liu, Duo; Wang, Yuhui; Dong, Mei; Guan, Shangwei; Wang, Yan; Sun, Haiming; Wu, Nan; Li, Su; Bai, Jing; Chen, Feng; Sun, Donglin; Jin, Yan

    2017-02-01

    To investigate whether cytokine genetic polymorphisms influence the outcome of diffuse large B cell lymphoma (DLBCL), we tested 337 consecutive DLBCL treated with CHOP or rituximab-CHOP (R-CHOP) from interleukin 10 (IL10), Bcl-2, and tumor necrosis factor (TNF)-α polymorphisms. Patients who carried the IL10 rs1800871 TT or rs1800872 AA genotype showed higher complete response (CR) and overall response rate (ORR) significantly. A longer progression-free survival (PFS) was observed in patients with IL10 rs1800871 TT (P = 0.017) or rs1800872 AA (P = 0.017) genotype after rituximab-based chemotherapy, and better PFS was also noted with Bcl-2 rs1801018 AA genotype in the CHOP group (P = 0.048). Furthermore, the R-CHOP group patients who carried the IL10 non-CCA haplotype had longer PFS (P = 0.030). Cox proportional hazards analyses demonstrated that the genotype TT of IL10 rs1800871 and AA plus AC of rs1800872 were predictive of longer PFS and event-free survival (EFS) in DLBCL patients treated with R-CHOP. And the Bcl-2 rs2279115 AA plus AC genotypes and rs1801018 GG genotype were risk factors for EFS in DLBCL patients treated with CHOP. In conclusion, the results reminded us those DLBCL patients with IL10 rs1800871 TT, rs1800872 AA, or IL10 non-CCA haplotype are likely to benefit from the therapy of rituximab-based chemotherapy.

  5. High concordance of gene expression profiling-correlated immunohistochemistry algorithms in diffuse large B-cell lymphoma, not otherwise specified.

    PubMed

    Hwang, Hee Sang; Park, Chan-Sik; Yoon, Dok Hyun; Suh, Cheolwon; Huh, Jooryung

    2014-08-01

    Diffuse large B-cell lymphoma (DLBCL) is classified into prognostically distinct germinal center B-cell (GCB) and activated B-cell subtypes by gene expression profiling (GEP). Recent reports suggest the role of GEP subtypes in targeted therapy. Immunohistochemistry (IHC) algorithms have been proposed as surrogates of GEP, but their utility remains controversial. Using microarray, we examined the concordance of 4 GEP-correlated and 2 non-GEP-correlated IHC algorithms in 381 DLBCLs, not otherwise specified. Subtypes and variants of DLBCL were excluded to minimize the possible confounding effect on prognosis and phenotype. Survival was analyzed in 138 cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP)-treated and 147 rituximab plus CHOP (R-CHOP)-treated patients. Of the GEP-correlated algorithms, high concordance was observed among Hans, Choi, and Visco-Young algorithms (total concordance, 87.1%; κ score: 0.726 to 0.889), whereas Tally algorithm exhibited slightly lower concordance (total concordance 77.4%; κ score: 0.502 to 0.643). Two non-GEP-correlated algorithms (Muris and Nyman) exhibited poor concordance. Compared with the Western data, incidence of the non-GCB subtype was higher in all algorithms. Univariate analysis showed prognostic significance for Hans, Choi, and Visco-Young algorithms and BCL6, GCET1, LMO2, and BCL2 in CHOP-treated patients. On multivariate analysis, Hans algorithm retained its prognostic significance. By contrast, neither the algorithms nor individual antigens predicted survival in R-CHOP treatment. The high concordance among GEP-correlated algorithms suggests their usefulness as reliable discriminators of molecular subtype in DLBCL, not otherwise specified. Our study also indicates that prognostic significance of IHC algorithms may be limited in R-CHOP-treated Asian patients because of the predominance of the non-GCB type.

  6. Thalidomide enhanced the efficacy of CHOP chemotherapy in the treatment of diffuse large B cell lymphoma: A phase II study

    PubMed Central

    Ji, Dongmei; Li, Qiu; Cao, Junning; Guo, Ye; Lv, Fangfang; Liu, Xiaojian; Wang, Biyun; Wang, Leiping; Luo, Zhiguo; Chang, Jianhua; Wu, Xianghua; Hong, Xiaonan

    2016-01-01

    Cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab (R-CHOP) is the standard treatment for patients with diffuse large B cell lymphoma (DLBCL). However, rituximab cannot be popularly applied in a considerable number of patients with DLBCL because of economic reasons. To develop a new regimen to improve the outcome of these patients is extremely important. In our study, sixty five patients with DLBCL were randomly assigned to thalidomide plus CHOP group (n=32) or to CHOP alone group (n=33). Objective response rates (ORR) and complete remission rates (CRR) were 96.7% and 80.6% in T-CHOP group versus 78.9 % and 57.8 % in CHOP group, respectively (P <0.05). At a median follow-up of 96 months, median PFS for T-CHOP group was still not reached yet, and in CHOP group it was 22.9 months (95% CI [0-50.4]). (P=0.163). Median overall survival (OS) for T-CHOP group was also not reached, and the estimated median OS for CHOP group was 83.5 months, the difference of OS between the two groups is not significant (p=0.263). But, in patients with Bcl-2 positive and Bcl-6 negative, the median PFS in T-CHOP group was longer than that in CHOP group (111.0 vs 8.5 months (P=0.017). In addition, thalidomide did not significantly increase the grade 3/4 toxicity of CHOP. We concluded that the addition of thalidomide to the CHOP regimen significantly improved the CRR and showed a trend of improving clinical outcome in patients with DLBCL, especially for patients with Bcl-2 positive and Bcl-6 negative B-cell phenotype, without increased toxicity. PMID:27129176

  7. Involved-Lesion Radiation Therapy After Chemotherapy in Limited-Stage Head-and-Neck Diffuse Large B Cell Lymphoma

    SciTech Connect

    Yu, Jeong Il; Nam, Heerim; Ahn, Yong Chan; Kim, Won Seog; Park, Keunchil; Kim, Seok Jin

    2010-10-01

    Purpose: To report treatment outcomes after combined-modality therapy in patients with Stage I/II head-and-neck (HN) diffuse large B cell lymphoma (DLBL). Methods and Materials: Eighty-six eligible patients received sequential chemotherapy and involved-lesion radiation therapy from 1995 to 2006. After a median of four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab-plus-CHOP chemotherapy, a median of 41.4 Gy was delivered to the known initial gross lesion with adequate margin (2 to 3 cm). Results: After a median follow-up of 57 months, eight treatment failures were observed: distant metastasis in 8 patients; and locoregional failure in 4 patients. Among the 4 patients with locoregional failure, 3 presented with in-field failures, and 1 both in-field and out-of-field failure (contralateral neck). Rates of overall survival (OS) and freedom from progression (FFP) at 10 years were 74.1% and 88.9%, respectively. There was no severe side effect except 1 patient with Grade 3 mucositis during and after completion of radiation therapy. Multivariate analyses showed that absence of B symptom (p = 0.022) and normal lactate dehydrogenase (p = 0.017) were related to favorable OS, age >60 years (p = 0.033) was related to favorable FFP, and international prognostic index of 0 or 1 was related to favorable OS (p = 0.003) and FFP (p = 0.03). Conclusion: This study demonstrated that patients with Stage I/II HN DLBL did not need whole-neck irradiation. Involved-lesion radiation therapy might reduce radiation toxicity with favorable treatment results.

  8. PD-L1 expression in EBV-negative diffuse large B-cell lymphoma: clinicopathologic features and prognostic implications

    PubMed Central

    Xing, Wei; Dresser, Karen; Zhang, Rui; Evens, Andrew M.; Yu, Hongbo; Woda, Bruce A.; Chen, Benjamin J.

    2016-01-01

    Programmed cell death ligand 1 (PD-L1) is a cell surface glycoprotein that regulates the cellular immune response and serves as a targetable immune checkpoint molecule. PD-L1 is expressed on tumor cells and the immune microenvironment of several human malignancies, including a subset of aggressive lymphomas. We sought to investigate further the clinical and pathologic features of EBV-negative diffuse large B-cell lymphoma (DLBCL) cases that express PD-L1. Immunohistochemical staining using an anti-PD-L1 monoclonal antibody was performed on DLBCL cases from 86 patients. These patients received standard chemotherapy treatment and were followed for up to 175 months. Overall, 14 cases (16%) were considered positive for PD-L1 in tumor cells. In comparison with PD-L1 negative cases, PD-L1 positive cases had a higher rate of non-GCB type (71% vs. 30%, P=0.0060), and higher Ann Arbor stage (II-IV) (100% vs. 73%, P=0.0327). No significant differences were seen in the immunohistochemical expression of BCL2, MYC, or Ki67. Patients with tumors expressing PD-L1 demonstrated inferior overall survival (OS) upon long term follow up (P=0.0447). Both age/sex-adjusted and multivariate analyses identified PD-L1 as an independent predictor for OS (P=0.0101 and P=0.0424). There was no significant difference, however, in terms of remission rates after first treatment, relapse rates, and progression free survival between the groups. Identification of DLBCL cases that express PD-L1 may serve to select a subset of patients that could further benefit from targeted immunotherapy. PMID:27527850

  9. A microRNA signature profile in EBV+ diffuse large B-cell lymphoma of the elderly

    PubMed Central

    de Andrade, Tathiana Azevedo; Evangelista, Adriane Feijo; Campos, Antonio Hugo Froes; Poles, Wagner Augusto; Borges, Natalia Morais; Camillo, Claudia Malheiros Coutinho; Soares, Fernando Augusto; Vassallo, Jose; Paes, Roberto Pinto; Zerbini, Maria Claudia; Scapulatempo, Cristovam; Alves, Antonio Correa

    2014-01-01

    Currently, there is no characteristic microRNA (miRNA) expression pattern in Epstein-Barr virus+ diffuse large B-cell lymphoma of the elderly (EBV+DLBCLe). This study aims to characterize a signature profile and identify miRNAs that can be used as biomarkers and alternative therapeutic targets for EBV+DLBCLe. Seventy-one DLBCL patients aged 50 years and older were included and four EBV+ and four EBV– samples were analyzed in two miRNA array platforms (pilot study). A larger multicenter cohort (29 EBV+DLBCLe and 65 EBV–DLBCL patients) was used to validate the results by real-time polymerase chain reaction. In the pilot study, 9% of DLBCL were EBV+DLBCLe by in situ hybridization. In multicenter study, EBV+DLBCLe group showed a predominance of non-germinal center B-cell origin. Overall survival duration of EBV+DLBCLe was significantly inferior to that of EBV–DLBCL patients. We found 10 deregulated miRNAs in the two groups, but only seven were statistically different. We confirmed overexpression of hsa-miR-126, hsa-miR-146a, hsa-miR-146b, hsa-miR-150, and hsa-miR-222 and underexpression of hsa-miR-151 in EBV+DLBCLe cases compared to EBV–DLBCL cases. Hsa-miR-146b and hsa-miR-222 showed high specificity for identifying EBV+DLBCLe. The present study proposed a miRNA signature for EBV+DLBCLe and our findings suggest that hsa-miR-146b and hsa-miR-222 could be biomarkers and therapeutic targets. PMID:25544772

  10. Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas

    PubMed Central

    Bognar, M K; Vincendeau, M; Erdmann, T; Seeholzer, T; Grau, M; Linnemann, J R; Ruland, J; Scheel, C H; Lenz, P; Ott, G; Lenz, G; Hauck, S M; Krappmann, D

    2016-01-01

    Constitutive activation of the antiapoptotic nuclear factor-κB (NF-κB) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-κB activation and promoted the stabilization of β-catenin. The β-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated β-catenin expression. In line, β-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased β-catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, β-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that β-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-κB target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis. PMID:26776161

  11. High miR-34a expression improves response to doxorubicin in diffuse large B-cell lymphoma.

    PubMed

    Marques, Sara Correia; Ranjbar, Benyamin; Laursen, Maria Bach; Falgreen, Steffen; Bilgrau, Anders Ellern; Bødker, Julie Støve; Jørgensen, Laura Krogh; Primo, Maria Nascimento; Schmitz, Alexander; Ettrup, Marianne Schmidt; Johnsen, Hans Erik; Bøgsted, Martin; Mikkelsen, Jacob Giehm; Dybkær, Karen

    2016-04-01

    The standard treatment for patients with diffuse large B-cell lymphoma (DLBCL) is the immunochemotherapy-based R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). Resistance to treatment, intrinsic or acquired, is observed in approximately 40% of patients with DLBCL, who thus require novel interventions to survive. To identify biomarkers for cytotoxic response assessment, microRNAs (miRNAs) associated with doxorubicin sensitivity were determined by combining global miRNA expression profiling with systematic dose-response screens in 15 human DLBCL cell lines. One candidate, miR-34a, was tested in functional in vitro studies and in vivo in a retrospective clinical cohort. High expression of miR-34a was observed in cell lines sensitive to doxorubicin, and upregulation of miR-34a is documented here to increase doxorubicin sensitivity in in vitro lentiviral transduction assays. High expression of miR-34a had a prognostic impact using overall survival as outcome. With risk stratification of DLBCL samples based on resistance gene signatures (REGS), doxorubicin-responsive samples had statistically significant upregulated miR-34a expression. Classification of the DLBCL samples into subset-specific B cell-associated gene signatures (BAGS) revealed differentiation-specific expression of miR-34a. Our data further support FOXP1 as a target of miR-34a, suggesting that downregulation of FOXP1 may sensitize DLBCL cells to doxorubicin. We conclude that miRNAs, in particular miR-34a, may have clinical utility in DLBCL patients as both predictive and prognostic biomarkers.

  12. Direct and indirect effects of enablers on HIV testing, initiation and retention in antiretroviral treatment and AIDS related mortality

    PubMed Central

    2017-01-01

    Background An enabling environment is believed to have significant and critical effects on HIV and AIDS program implementation and desired outcomes. This paper estimates the paths, directionality, and direct and indirect associations between critical enablers with antiretroviral treatment (ART) coverage and to AIDS-related mortality. Methods Frameworks that consider the role of enablers in HIV and AIDS programs were systematically reviewed to develop a conceptual model of interaction. Measurements for constructs of the model were pooled from the latest publicly available data. A hypothetical model, including latent/unobserved factors and interaction of enablers, program activities and outcomes, was analyzed cross-sectionally with structural equation modeling. Coefficients of the model were used to estimate the indirect associations of enablers to treatment coverage and the subsequent associated impact on AIDS related mortality. Findings The model’s fit was adequate (RMSEA = 0·084, 90% CI [0·062, 0·104]) and the indirect effects of enablers on outcomes were measured. Enablers having significant associations with increased ART coverage were social/financial protection, governance, anti-discrimination, gender equality, domestic AIDS spending, testing service delivery, and logistics. Interpretation Critical enablers are significantly correlated to outcomes like ART coverage and AIDS related mortality. Even while this model does not allow inference on causality, it provides directionality and magnitude of the significant associations. PMID:28225790

  13. Creating Social Spaces to Tackle AIDS-Related Stigma: Reviewing the Role of Church Groups in Sub-Saharan Africa

    PubMed Central

    Skovdal, M.; Gibbs, A.

    2012-01-01

    An expanding body of literature explores the role of African church groups in facilitating or hindering the support of people living with AIDS and challenging or contributing to HIV/AIDS-related stigma. Treating church groups as social spaces in which HIV/AIDS-related stigma may potentially be challenged, we systematically review this literature, identifying five themes that highlight the complex and contradictory role of the church as a potential agent of health-enhancing social change. In many ways the church perpetuates HIV/AIDS-related stigma through (i) moralistic attitudes and (ii) its reinforcement of conservative gender ideologies. However some churches have managed move towards action that makes a more positive contribution to HIV/AIDS management through (iii) promoting various forms of social control for HIV prevention, (iv) contributing to the care and support of the AIDS-affected and (v) providing social spaces for challenging stigmatising ideas and practices. We conclude that church groups, including church leadership, can play a key role in facilitating or hindering the creation of supportive social spaces to challenge stigma. Much work remains to be done in developing deeper understandings of the multi-layered factors that enable some churches, but not others, to respond effectively to HIV/AIDS. PMID:20668927

  14. Use of subsequent PET/CT in diffuse large B-cell lymphoma patients in complete remission following primary therapy.

    PubMed

    Zhang, Xu; Fan, Wei; Xia, Zhong-Jun; Hu, Ying-Ying; Lin, Xiao-Ping; Zhang, Ya-Rui; Li, Zhi-Ming; Liang, Pei-Yan; Li, Yuan-Hua

    2015-02-01

    Interim 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (I-PET/CT) is a powerful tool for monitoring the response to therapy in diffuse large B-cell lymphoma (DLBCL). This retrospective study aimed to determine when and how to use I-PET/CT in DLBCL. A total of 197 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were enrolled between October 2005 and July 2011; PET/CT was performed at the time of diagnosis (PET/CT0), after 2 and 4 cycles of chemotherapy (PET/CT2 and PET/CT4, respectively), and at the end of treatment (F-PET/CT). According to the International Harmonization Project for Response Criteria in Lymphoma, 110 patients had negative PET/CT2 scans, and 87 had positive PET/CT2 scans. The PET/CT2-negative patients had significantly higher 3-year progression-free survival rate (75.8% vs. 38.2%) and 3-year overall survival rate (93.5% vs. 55.6%) than PET/CT2-positive patients. All PET/CT2-negative patients remained negative at PET/CT4, but 3 were positive at F-PET/CT. Among the 87 PET/CT2-positive patients, 57 remained positive at F-PET/CT, and 32 progressed during chemotherapy (15 at PET/CT4 and 17 at F-PET/CT). Comparing PET/CT4 with PET/CT0, 7 patients exhibited progression, and 8 achieved partial remission. Comparing F-PET/CT with PET/CT0, 10 patients exhibited progression, and 7 achieved partial remission. In conclusion, our results indicate that I-PET/CT should be performed after 2 rather than 4 cycles of immunochemotherapy in DLBCL patients. There is a limited role for subsequent PET/CT in the detection of relapse in PET/CT2-negative patients, but repeat PET/CT is required if the PET/CT2 findings are positive.

  15. NASA/DOD Aerospace Knowledge Diffusion Research Project. Paper 62: The Influence of Knowledge Diffusion on Aeronautics Innovation: The Research, Development, and Production of Large Commercial Aircraft in France, Germany, and the United Kingdom

    NASA Technical Reports Server (NTRS)

    Golich, Vicki L.; Pinelli, Thomas E.

    1997-01-01

    This paper focuses on how European public policies-individually and collectively - influence the diffusion of knowledge and technology. It begins with an overview of the roles played historically and currently by European governments in the Research, Development and Production (RD&P) of Large Commercial Aircraft (LCA). The analytical framework brings together literature from global political economy, comparative politics, business management, and science and technology policy studies. It distinguishes between the production of knowledge, on the one hand, and the dissemination of knowledge, on the other. France, Germany, and the United Kingdom serve as the analytical cases. The paper concludes with a call for additional research in this area, some tentative lessons learned, and a discussion of the consequences of national strategies and policies for the diffusion of knowledge and technology in an era of globalizaton.

  16. NASA/DOD Aerospace Knowledge Diffusion Research Project. Paper 62: The Influence of Knowledge Diffusion on Aeronautics Innovation: The Research, Development, and Production of Large Commercial Aircraft in France, Germany, and the United Kingdom

    NASA Technical Reports Server (NTRS)

    Pinelli, Thomas E.; Golich, Vicki L.

    1997-01-01

    This paper focuses on how European public policies-individually and collectively - influence the diffusion of knowledge and technology. It begins with an overview of the roles played historically and currently by European governments in the research, development and production (RD&P) of large commercial aircraft (LCA). The analytical framework brings together literature from global political economy, comparative politics, business management, and science and technology policy studies. It distinguishes between the production of knowledge, on the one hand, and the dissemination of knowledge, on the other. France, Germany, and the United Kingdom serve as the analytical cases. The paper concludes with a call for additional research in this area, some tentative lessons learned, and a discussion of the consequences of national strategies and policies for the diffusion of knowledge and technology in an era of globalization.

  17. Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO).

    PubMed

    Peñalver, Francisco-Javier; Sancho, Juan-Manuel; de la Fuente, Adolfo; Olave, María-Teresa; Martín, Alejandro; Panizo, Carlos; Pérez, Elena; Salar, Antonio; Orfao, Alberto

    2017-02-01

    Diffuse large B-cell lymphoma patients have a 5% overall risk of central nervous system events (relapse or progression), which account for high morbidity and frequently fatal outcomes,(1) and shortened overall survival of <6 months.(2) Early diagnosis of central nervous system events is critical for successful treatment and improved prognosis. Identification of patients at risk of central nervous system disease is critical to accurately identify candidates for central nervous system prophylaxis vs.

  18. A novel orally available inhibitor of focal adhesion signaling increases survival in a xenograft model of diffuse large B-cell lymphoma with central nervous system involvement.

    PubMed

    Bosch, Rosa; Moreno, María José; Dieguez-Gonzalez, Rebeca; Céspedes, María Virtudes; Gallardo, Alberto; Trias, Manuel; Grañena, Albert; Sierra, Jorge; Casanova, Isolda; Mangues, Ramon

    2013-08-01

    Central nervous system dissemination is a relatively uncommon but almost always fatal complication in diffuse large B-cell lymphoma patients. Optimal therapy for central nervous involvement in this malignancy has not been established. In this paper, we aimed to evaluate the therapeutic effect of E7123, a celecoxib derivative that inhibits focal adhesion signaling, in a novel xenograft model of diffuse large B-cell lymphoma with central nervous system involvement. Cells obtained after disaggregation of HT subcutaneous tumors (HT-SC cells) were intravenously injected in NOD/SCID mice. These mice received oral vehicle or 75 mg/kg of E7123 daily until they were euthanized for weight loss or signs of sickness. The antitumor effect of E7123 was validated in an independent experiment using a bioluminescent mouse model. Intravenously injected HT-SC cells showed higher take rate and higher central nervous system tropism (associated with increased expression of β1-integrin and p130Cas proteins) than HT cells. The oral administration of E7123 significantly increased survival time in 2 independent experiments using mice injected with unmodified or bioluminescent HT-SC cells. We have developed a new xenograft model of diffuse large B-cell lymphoma with central nervous system involvement that can be used in the pre-clinical evaluation of new drugs for this malignancy. E7123 is a new, well-tolerated and orally available therapeutic agent that merits further investigation since it may improve current management of diffuse large B-cell lymphoma patients with central nervous system involvement.

  19. Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma

    PubMed Central

    Shah, Phalgoon A.; Carmichael, Mark G.; Ferguson, Tomas M.

    2016-01-01

    Hepatitis C virus (HCV) infection is associated with the development of non-Hodgkin lymphomas. For aggressive lymphomas, such as diffuse large B-cell lymphoma (DLBCL), treatment of HCV infection is typically deferred in treatment-naive patients until after completion of lymphoma therapy [1, 2]. We report a case of HCV-associated stage IV DLBCL successfully treated concurrently using chemoimmunotherapy and a sofosbuvir-based antiviral regimen. PMID:28018926

  20. The contribution of HGAL/GCET2 in immunohistological algorithms: a comparative study in 424 cases of nodal diffuse large B-cell lymphoma.

    PubMed

    Gualco, Gabriela; Bacchi, Lívia M; Domeny-Duarte, Pollyanna; Natkunam, Yasodha; Bacchi, Carlos E

    2012-11-01

    Diffuse large B-cell lymphoma can be subclassified into at least two molecular subgroups by gene expression profiling: germinal center B-cell like and activated B-cell like diffuse large B-cell lymphoma. Several immunohistological algorithms have been proposed as surrogates to gene expression profiling at the level of protein expression, but their reliability has been an issue of controversy. Furthermore, the proportion of misclassified cases of germinal center B-cell subgroup by immunohistochemistry, in all reported algorithms, is higher compared with germinal center B-cell cases defined by gene expression profiling. We analyzed 424 cases of nodal diffuse large B-cell lymphoma with the panel of markers included in the three previously described algorithms: Hans, Choi, and Tally. To test whether the sensitivity of detecting germinal center B-cell cases could be improved, the germinal center B-cell marker HGAL/GCET2 was also added to all three algorithms. Our results show that the inclusion of HGAL/GCET2 significantly increased the detection of germinal center B-cell cases in all three algorithms (P<0.001). The proportions of germinal center B-cell cases in the original algorithms were 27%, 34%, and 19% for Hans, Choi, and Tally, respectively. In the modified algorithms, with the inclusion of HGAL/GCET2, the frequencies of germinal center B-cell cases were increased to 38%, 48%, and 35%, respectively. Therefore, HGAL/GCET2 protein expression may function as a marker for germinal center B-cell type diffuse large B-cell lymphoma. Consideration should be given to the inclusion of HGAL/GCET2 analysis in algorithms to better predict the cell of origin. These findings bear further validation, from comparison to gene expression profiles and from clinical/therapeutic data.

  1. Highly elevated serum lactate dehydrogenase is associated with central nervous system relapse in patients with diffuse large B-cell lymphoma: Results of a multicenter prospective cohort study.

    PubMed

    Kim, Seok Jin; Hong, Jun Sik; Chang, Myung Hee; Kim, Jeong-A; Kwak, Jae-Yong; Kim, Jin Seok; Yoon, Dok Hyun; Lee, Won Sik; Do, Young Rok; Kang, Hye Jin; Eom, Hyeon-Seok; Park, Yong; Won, Jong-Ho; Mun, Yeung-Chul; Kim, Hyo Jung; Kwon, Jung Hye; Kong, Jee Hyun; Oh, Sung Yong; Lee, Sunah; Bae, Sung Hwa; Yang, Deok-Hwan; Jun, Hyun Jung; Kim, Yang Soo; Yun, Hwan Jung; Lee, Soon Il; Kim, Min Kyoung; Park, Eun Kyung; Kim, Won Seog; Suh, Cheolwon

    2016-11-01

    Central nervous system involvement remains a challenging issue in the treatment of patients with diffuse large B-cell lymphoma. We conducted a prospective cohort study with newly diagnosed diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone to identify incidence and risk factors for central nervous system involvement. Among 595 patients, 279 patients received pre-treatment central nervous system evaluation, and 14 patients had central nervous system involvement at diagnosis (2.3% out of entire patients and 5.0% out of the 279 patients). For those patients, median follow-up duration was 38.2 months and some of them achieved long-term survival. Out of 581 patients who did not have central nervous system involvement at diagnosis, 26 patients underwent secondary central nervous system relapse with a median follow-up of 35 months, and the median time to central nervous system involvement was 10.4 months (range: 3.4-29.2). Serum lactate dehydrogenase > ×3 upper limit of normal range, the Eastern Cooperative Oncology Group performance status ≥ 2, and involvement of sinonasal tract or testis, were independent risk factors for central nervous system relapse in multivariate analysis. Our study suggests that enhanced stratification of serum lactate dehydrogenase according to the National Comprehensive Cancer Network-International Prognostic Index may contribute to better prediction for central nervous system relapse in patients with diffuse large B-cell lymphoma. This trial was registered at clinicaltrials.gov identifier: 01202448.

  2. Time Dependent Density Functional Theory Calculations of Large Compact PAH Cations: Implications for the Diffuse Interstellar Bands

    NASA Technical Reports Server (NTRS)

    Weisman, Jennifer L.; Lee, Timothy J.; Salama, Farid; Gordon-Head, Martin; Kwak, Dochan (Technical Monitor)

    2002-01-01

    We investigate the electronic absorption spectra of several maximally pericondensed polycyclic aromatic hydrocarbon radical cations with time dependent density functional theory calculations. We find interesting trends in the vertical excitation energies and oscillator strengths for this series containing pyrene through circumcoronene, the largest species containing more than 50 carbon atoms. We discuss the implications of these new results for the size and structure distribution of the diffuse interstellar band carriers.

  3. Framing, agenda setting, and disease phobia of AIDS-related coverage in the South Korean mass media.

    PubMed

    Jung, Minsoo

    2013-01-01

    There has been little research on the concrete role of the press in discourses on AIDS. This study investigated the AIDS discourses created by the major media. In particular, from the perspective of the agenda-setting theory, it examines differences in the framing of AIDS-related news depending on the political orientation and news sources of the press. This study analyzed the thematic frames and news sources implied by AIDS-related coverage. The 2 major media representing conservatism and progressivism were selected as the objects of analysis. As for the search engine for content analysis, the Korean Integrated Newspaper Database System was used, and 151 articles containing "AIDS" or "HIV" over 5 years from January 2005 to December 2010 were analyzed. According to the results of the analysis, there were the 6 following frames: aid/support, accident, human rights, risk, prevention, and biomedicine. Whereas the conservative press in South Korea continued to frame AIDS in the traditional way, the progressive press tended relatively more often to attempt new agenda setting, from the perspective of human rights and inequality. However, both newspaper companies tended mostly to select experts as the sources of AIDS news, thus continuing to exclude infectees and civil and society organizations.

  4. Ethnobotanical Study of Plants Used in the Management of HIV/AIDS-Related Diseases in Livingstone, Southern Province, Zambia

    PubMed Central

    Chinsembu, Kazhila C.

    2016-01-01

    Faced with critical shortages of staff, long queues, and stigma at public health facilities in Livingstone, Zambia, persons who suffer from HIV/AIDS-related diseases use medicinal plants to manage skin infections, diarrhoea, sexually transmitted infections, tuberculosis, cough, malaria, and oral infections. In all, 94 medicinal plant species were used to manage HIV/AIDS-related diseases. Most remedies are prepared from plants of various families such as Combretaceae, Euphorbiaceae, Fabaceae, and Lamiaceae. More than two-thirds of the plants (mostly leaves and roots) are utilized to treat two or more diseases related to HIV infection. Eighteen plants, namely, Achyranthes aspera L., Lannea discolor (Sond.) Engl., Hyphaene petersiana Klotzsch ex Mart., Asparagus racemosus Willd., Capparis tomentosa Lam., Cleome hirta Oliv., Garcinia livingstonei T. Anderson, Euclea divinorum Hiern, Bridelia cathartica G. Bertol., Acacia nilotica Delile, Piliostigma thonningii (Schumach.) Milne-Redh., Dichrostachys cinerea (L.) Wight and Arn., Abrus precatorius L., Hoslundia opposita Vahl., Clerodendrum capitatum (Willd.) Schumach., Ficus sycomorus L., Ximenia americana L., and Ziziphus mucronata Willd., were used to treat four or more disease conditions. About 31% of the plants in this study were administered as monotherapies. Multiuse medicinal plants may contain broad-spectrum antimicrobial agents. However, since widely used plants easily succumb to the threats of overharvesting, they need special protocols and guidelines for their genetic conservation. There is still need to confirm the antimicrobial efficacies, pharmacological parameters, cytotoxicity, and active chemical ingredients of the discovered plants. PMID:27069489

  5. Recruiting Chinese American adolescents to HIV/AIDS-related research: a lesson learned from a cross-sectional study.

    PubMed

    Lee, Yi-Hui; Salman, Ali; Wang, Fan

    2012-02-01

    The purpose of this article was to report identified barriers and challenges experienced in the recruiting process of Chinese American adolescents to a cross-sectional HIV/AIDS-related study. Snowball sampling method was used to recruit Chinese American adolescents from Chinese American communities in a U.S. Midwestern state. Barriers and challenges to recruitment were reviewed and analyzed from Chinese cultural perspectives in the hope of aiding researchers and health care providers understand and facilitate future recruitment of Chinese Americans for HIV/AIDS prevention studies. Barriers to recruitment were found related to the taboo topic of sexual issues in Chinese culture, unawareness and denial of HIV/AIDS risks, authoritarian parenting style in Chinese culture, and the required active consents. Facilitating factors of recruiting Chinese American adolescents to future HIV/AIDS prevention research or intervention programs are discussed. Information provided in this article may increase nurses' awareness of various barriers that they might encounter when they conduct research or address HIV/AIDS-related topics of Chinese American adolescents.

  6. Eradication of HCV and non-liver-related non-AIDS-related events in HIV/HCV coinfection.

    PubMed

    Berenguer, Juan; Rodríguez-Castellano, Elena; Carrero, Ana; Von Wichmann, Miguel A; Montero, Marta; Galindo, María J; Mallolas, Josep; Crespo, Manuel; Téllez, María J; Quereda, Carmen; Sanz, José; Barros, Carlos; Tural, Cristina; Santos, Ignacio; Pulido, Federico; Guardiola, Josep M; Rubio, Rafael; Ortega, Enrique; Montes, María L; Jusdado, Juan J; Gaspar, Gabriel; Esteban, Herminia; Bellón, José M; González-García, Juan

    2017-01-21

    We assessed non-liver-related non-AIDS-related (NLR-NAR) events and mortality in a cohort of HIV/HCV-coinfected patients treated with interferon and ribavirin between 2000 and 2008. The censoring date was May 31, 2014. Cox regression analysis was performed to assess the adjusted hazard rate (HR) of overall death in responders and non-responders. Fine and Gray regression analysis was conducted to determine the adjusted sub-hazard rate (sHR) of NLR deaths and NLR-NAR events considering death as the competing risk. The NLR-NAR events analyzed included diabetes mellitus, chronic renal failure, cardiovascular events, NLR-NAR cancer, bone events, and non-AIDS-related infections. The variables for adjustment were age, sex, prior AIDS, HIV-transmission category, nadir CD4+ T-cell count, antiretroviral therapy, HIV-RNA, liver fibrosis, HCV genotype, and exposure to specific anti-HIV drugs. Of the 1,625 patients included, 592 (36%) had a sustained viral response (SVR). After a median five-year follow-up, SVR was found to be associated with a significant decrease in the hazard of diabetes mellitus (sHR 0.57 [95% CI, 0.35 - 0.93] P= .024) and decline in the hazard of chronic renal failure close to the threshold of significance (sHR 0.43 [95% CI, 0.17 - 1.09], P=.075).

  7. A situational analysis of HIV/AIDS-related discrimination in Kerala, India.

    PubMed

    Elamon, J

    2005-07-01

    Due to its large population, India has a substantial proportion of the world's HIV infections. Recent evidence suggests that the virus is moving into the general population from high-risk groups. Despite this, a mentality of 'us' and 'them' continues to prevail, where PLWHA are marginalised from mainstream society. Focusing on the area of health care, this study, through an analysis of legislative policy, written regulations and interviews with key informants and direct witnesses aims to map the forms of structural discrimination that inform the lives of PLWHA. Study findings indicate that a lack of clearly enunciated and enforced legislation (which is in some instances clearly discriminatory), coupled with an absence of written internal policy, leaves room for selective interpretation, which in turn creates the opportunities for discriminatory behaviours to be perpetuated against PLWHA. The paper concludes with a call for better educational training of medical staff and the improvement of existing legislature.

  8. Migration of large earthquakes along the San Jacinto Fault; Stress diffusion from the 1857 Fort Tejon Earthquake

    NASA Astrophysics Data System (ADS)

    Rydelek, Paul A.; Sacks, I. Selwyn

    Historic and modern catalogs of seismicity in California suggest a migration of earthquakes (M ≥ 5.6) along the San Jacinto Fault; these events appear to travel down the fault with a migration speed of 1.7 km/year (Sanders [1993]). This migration is explained by postseismic strain diffusion due to viscoelastic relaxation from the great Fort Tejon earthquake in 1857. We model this postseismic effect and find that significant stress diffuses down the San Jacinto fault for distances in excess of 200 km and the corresponding migration may be a result of Coulomb triggering from this stress perturbation. The level of postseismic stress that seems to be the trigger level for most of the events is of order 1 bar. Since the temporal evolution of the postseismic strain field is mainly dependent on the inelastic properties of the lower crust and uppermost mantle, the observed migration enables a viscosity estimate of ˜4 × 1018 Pas for this region of California.

  9. Effect of local velocity on diffusion-induced stress in large-deformation electrodes of lithium-ion batteries

    NASA Astrophysics Data System (ADS)

    Li, Yong; Zhang, Kai; Zheng, Bailin; Yang, Fuqian

    2016-07-01

    In this work, the contribution of local velocity to the resultant flux of lithium in lithium-ion battery is introduced into the diffusion equation to describe the migration of lithium in the active material of electrodes. The effect of the local velocity on the stress evolution in a spherical electrode made of silicon is analyzed, using the derived diffusion equation and nonlinear theory of elasticity. Two boundary conditions at the surface of the electrode, which represent two extreme conditions of real electrode materials, are used in the stress analysis: one is stress-free, and the other is immobile. The numerical results with the stress-free boundary condition suggest that the effect of the local velocity on the distribution of radial stress and hoop stress increases with the increase of time and the effect of the local velocity on the distribution of lithium is relatively small. In comparison with the results without the effect of the local velocity, the effect of the local velocity is negligible for the immobile boundary condition. The numerical result shows that the use of the immobile boundary condition leads to the decrease of von-Mises stress, which likely will retard the mechanical degradation of electrode and improve the electrochemical performance of lithium-ion battery.

  10. Measurements of beam halo diffusion and population density in the Tevatron and in the Large Hadron Collider

    SciTech Connect

    Stancari, Giulio

    2015-03-01

    Halo dynamics influences global accelerator performance: beam lifetimes, emittance growth, dynamic aperture, and collimation efficiency. Halo monitoring and control are also critical for the operation of high-power machines. For instance, in the high-luminosity upgrade of the LHC, the energy stored in the beam tails may reach several megajoules. Fast losses can result in superconducting magnet quenches, magnet damage, or even collimator deformation. The need arises to measure the beam halo and to remove it at controllable rates. In the Tevatron and in the LHC, halo population densities and diffusivities were measured with collimator scans by observing the time evolution of losses following small inward or outward collimator steps, under different experimental conditions: with single beams and in collision, and, in the case of the Tevatron, with a hollow electron lens acting on a subset of bunches. After the LHC resumes operations, it is planned to compare measured diffusivities with the known strength of transverse damper excitations. New proposals for nondestructive halo population density measurements are also briefly discussed.

  11. AIDS-Related Stigma and Mental Disorders among People Living with HIV: A Cross-Sectional Study in Cambodia

    PubMed Central

    Yi, Siyan; Chhoun, Pheak; Suong, Samedy; Thin, Kouland; Brody, Carinne; Tuot, Sovannary

    2015-01-01

    Background AIDS-related stigma and mental disorders are the most common conditions in people living with HIV (PLHIV). We therefore conducted this study to examine the association of AIDS-related stigma and discrimination with mental disorders among PLHIV in Cambodia. Methods A two-stage cluster sampling method was used to select 1,003 adult PLHIV from six provinces. The People Living with HIV Stigma Index was used to measure stigma and discrimination, and a short version of general health questionnaire (GHQ-12) was used to measure mental disorders. Multivariate logistic regression analysis was conducted. Results The reported experiences of discrimination in communities in the past 12 months ranged from 0.8% for reports of being denied health services to 42.3% for being aware of being gossiped about. Internal stigma was also common ranging from 2.8% for avoiding going to a local clinic and/or hospital to 59.6% for deciding not to have (more) children. The proportions of PLHIV who reported fear of stigma and discrimination ranged from 13.9% for fear of being physically assaulted to 34.5% for fear of being gossiped about. The mean score of GHQ-12 was 3.2 (SD = 2.4). After controlling for several potential confounders, higher levels of mental disorders (GHQ-12≥ 4) remained significantly associated with higher levels of experiences of stigma and discrimination in family and communities (AOR = 1.9, 95% CI = 1.4–2.6), higher levels of internal stigma (AOR = 1.7, 95% CI = 1.2–2.3), and higher levels of fear of stigma and discrimination in family and communities (AOR = 1.5, 95% CI = 1.1–2.2). Conclusions AIDS-related stigma and discrimination among PLHIV in Cambodia are common and may have potential impacts on their mental health conditions. These findings indicate a need for community-based interventions to reduce stigma and discrimination in the general public and to help PLHIV to cope with this situation. PMID:25806534

  12. Topotecan Hydrochloride in Treating Children With Meningeal Cancer That Has Not Responded to Previous Treatment

    ClinicalTrials.gov

    2013-02-20

    AIDS-related Diffuse Large Cell Lymphoma; AIDS-related Diffuse Mixed Cell Lymphoma; AIDS-related Diffuse Small Cleaved Cell Lymphoma; AIDS-related Immunoblastic Large Cell Lymphoma; AIDS-related Lymphoblastic Lymphoma; AIDS-related Peripheral/Systemic Lymphoma; AIDS-related Primary CNS Lymphoma; AIDS-related Small Noncleaved Cell Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; HIV-associated Hodgkin Lymphoma; Leptomeningeal Metastases; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

  13. Diffuse reflectance spectroscopy in Barrett's esophagus: developing a large field-of-view screening method discriminating dysplasia from metaplasia.

    PubMed

    Douplik, Alexandre; Zanati, Simon; Saiko, Guennadi; Streutker, Catherine; Loshchenov, Maxim; Adler, Desmond; Cho, Sarah; Chen, Dean; Cirocco, Maria; Marcon, Norman; Fengler, John; Wilson, Brian C

    2014-05-01

    We evaluated diffuse reflectance spectroscopy implemented as a small field-of-view technique for discrimination of dysplasia from metaplasia in Barrett's esophagus as an adjuvant to autofluorescence endoscopy. Using linear discriminant analysis on 2579 spectra measured in 54 patients identified an optimum a 4-wavelength classifier (at 485, 513, 598 and 629 nm). Sensitivity and specificity for a test data set were 0.67 and 0.85, respectively. Spectroscopic results show that this technique could be implemented in wide-field imaging mode to improve the accuracy of existing endoscopy techniques for finding early pre-malignant lesions in Barrett's esophagus. Results show that the discrimination occurs likely due to redistribution of blood content in the tissue sensed by the optical probing with the wavelength-dependent sampling depth.

  14. Specificity of anti-lymphocyte antibodies in sera from patients with AIDS-related complex (ARC) and healthy homosexuals.

    PubMed Central

    Warren, R Q; Johnson, E A; Donnelly, R P; Lavia, M F; Tsang, K Y

    1988-01-01

    The presence and specificity of anti-lymphocyte antibodies (ALA) was investigated in sera from male homosexuals with AIDS-Related Complex (ARC) as well as healthy homosexuals. Individuals in the healthy homosexual group had no detectable antibodies to human immunodeficiency virus (HIV). Antibodies reactive with normal peripheral blood mononuclear cells were detected by Western blot analysis in sera from both groups of homosexuals. Of those individuals whose sera contained ALA, 71% of ARC patients and 83% of healthy homosexuals had antibodies recognizing a 73 kilodalton (kD) molecule. ALA present in ARC sera reacted with CD3+, CD4+ and CD8+ lymphocytes while little reactivity with B cells was observed. Our results indicate that ALA appear in homosexuals prior to HIV infection and are reactive primarily with T lymphocytes. A 73 kD structure associated with the T cell membrane is frequently the target for these antibodies. Images Fig. 1 Fig. 2 Fig. 3 PMID:3052941

  15. Highly elevated serum lactate dehydrogenase is associated with central nervous system relapse in patients with diffuse large B-cell lymphoma: Results of a multicenter prospective cohort study

    PubMed Central

    Kim, Seok Jin; Hong, Jun Sik; Chang, Myung Hee; Kim, Jeong-A; Kwak, Jae-Yong; Kim, Jin Seok; Yoon, Dok Hyun; Lee, Won Sik; Do, Young Rok; Kang, Hye Jin; Eom, Hyeon-Seok; Park, Yong; Won, Jong-Ho; Mun, Yeung-Chul; Kim, Hyo Jung; Kwon, Jung Hye; Kong, Jee Hyun; Oh, Sung Yong; Lee, Sunah; Bae, Sung Hwa; Yang, Deok-Hwan; Jun, Hyun Jung; Kim, Yang Soo; Yun, Hwan Jung; Il Lee, Soon; Kim, Min Kyoung; Park, Eun Kyung; Kim, Won Seog; Suh, Cheolwon

    2016-01-01

    Central nervous system involvement remains a challenging issue in the treatment of patients with diffuse large B-cell lymphoma. We conducted a prospective cohort study with newly diagnosed diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone to identify incidence and risk factors for central nervous system involvement. Among 595 patients, 279 patients received pre-treatment central nervous system evaluation, and 14 patients had central nervous system involvement at diagnosis (2.3% out of entire patients and 5.0% out of the 279 patients). For those patients, median follow-up duration was 38.2 months and some of them achieved long-term survival. Out of 581 patients who did not have central nervous system involvement at diagnosis, 26 patients underwent secondary central nervous system relapse with a median follow-up of 35 months, and the median time to central nervous system involvement was 10.4 months (range: 3.4–29.2). Serum lactate dehydrogenase > ×3 upper limit of normal range, the Eastern Cooperative Oncology Group performance status ≥ 2, and involvement of sinonasal tract or testis, were independent risk factors for central nervous system relapse in multivariate analysis. Our study suggests that enhanced stratification of serum lactate dehydrogenase according to the National Comprehensive Cancer Network-International Prognostic Index may contribute to better prediction for central nervous system relapse in patients with diffuse large B-cell lymphoma. This trial was registered at clinicaltrials.gov identifier: 01202448. PMID:27713132

  16. Altered natural history of AIDS-related opportunistic infections in the era of potent combination antiretroviral therapy.

    PubMed

    Jacobson, M A; French, M

    1998-01-01

    Since potent HIV protease inhibitor drugs became widely available in early 1996, many HIV clinical specialists have noted a marked decrease in the occurrence of AIDS-related opportunistic infections, and some specialists have reported unusual clinical presentations and manifestations of previously common opportunistic infections. In this article, we will review (1) the available data regarding recent trends in AIDS-related opportunistic infections incidence and manifestations, (2) clinical and immunologic evidence that potent combination antiretroviral therapy can alter the natural history of these opportunistic infections, and (3) the implications of these findings for current patient management practice and future clinical and immunologic research. As a preface to this review, however, it is important to acknowledge that any evaluation of the potential benefit of potent combination antiretroviral therapy in reducing the risk of serious opportunistic infections can be confounded by the concomitant use of prophylactic antimicrobial agents co-administered to prevent specific opportunistic infections. For example, it is standard clinical practice to administer trimethoprim-sulfamethoxazole (or another agent if trimethoprim-sulfamethoxazole cannot be tolerated) to patients with an absolute CD4 lymphocyte count < 200 cells/microliters, unexplained chronic fever or a history of oropharyngeal candidiasis. Similarly, specific antimicrobial prophylaxis to prevent disseminated Mycobacterium avium complex (MAC) infection in patients with absolute CD4 counts < 50 cells/microliters is also a widely recommended guideline. Although the relative efficacies of specific antimicrobial prophylaxis regimens in preventing the most common life- and sight-threatening opportunistic infectious complications of AIDS [Pneumocystis carinii pneumonia (PCP), disseminated MAC infection, and cytomegalovirus (CMV) retinitis] are now well established, these relative efficacies were established in

  17. Somatic mutation of EZH2 (Y641) in follicular and diffuse large B-cell lymphomas of germinal center origin | Office of Cancer Genomics

    Cancer.gov

    Morin et al. describe recurrent somatic mutations in EZH2, a polycomb group oncogene. The mutation, found in the SET domain of this gene encoding a histone methyltransferase, is found only in a subset of lymphoma samples. Specifically, EZH2 mutations are found in about 12% of follicular lymphomas (FL) and almost 23% of diffuse large B-cell lymphomas (DLBCL) of germinal center origin. This paper goes on to demonstrate that altered EZH2 proteins, corresponding to the most frequent mutations found in human lymphomas, have reduced activity using in vitro histone methylation assays.

  18. A rare case of the upper extremity diffuse large B-cell lymphoma mimicking soft tissue sarcoma in an elderly patient

    PubMed Central

    Mamorska-Dyga, Aleksandra; Ronny, Faisal M. H.; Puccio, Carmelo; Islam, Humayun

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, with about 30% of new cases presenting with extranodal disease. Lesions originating from soft tissues of the upper extremities are extremely rare and may mimic other malignancies like sarcoma. We present a case of an elderly patient with right upper extremity (RUE) mass which was proven to be DLBCL instead of sarcoma. We emphasize the increasing need for investigating new therapeutic options for patients of extreme age and/or with underlying heart disease. PMID:27486587

  19. Mantle cell lymphoma and diffuse large B-cell lymphoma of the testis: a unique case of composite non-Hodgkin lymphoma.

    PubMed

    Andhavarapu, Swati; Crozier, Jennifer A; Jiang, Liuyan; Sher, Taimur

    2014-12-01

    Primary testicular non-Hodgkin lymphoma (NHL) is a rare entity with the most common histologic subtype consisting of diffuse large B-cell lymphoma (DLBCL). Patients with primary testicular lymphoma (PTL) have a poor prognosis and a higher propensity for relapse. Also rare are composite lymphomas (CL) defined as two or more morphologically and phenotypically distinct lymphomas coexisting in a single organ or tissue. Here we present the first reported case of primary testicular composite lymphoma consisting of DLBCL and mantle cell lymphoma (MCL).

  20. Large format cylindrical lens films formed by roll-to-roll ultraviolet embossing and applications as diffusion films

    NASA Astrophysics Data System (ADS)

    Shan, X. C.; Liu, T.; Mohaime, M.; Salam, B.; Liu, Y. C.

    2015-03-01

    A roll-to-roll (R2R) ultraviolet (UV) embossing system has been developed for manufacturing micro features on continuous flexible films. The R2R UV embossing system, which has an embossing roller of 160 mm in diameter, can handle flexible polymer films with a width up to 500 mm and thickness ranging from 0.05 to 0.5 mm. A metal sheet template with micro features on its surface is mounted to the embossing roller and used as embossing mould. A slot die coating unit that has a coating width of 250 mm is used to deposit liquid UV curable resin on polymer films and coating thickness ranging from 10 to 50 µm has been achieved. Continuous roll-to-roll UV embossing is conducted and optical films with cylindrical lens arrays (curvature radius = 112  ±  2 µm, sag height = 28  ±  0.5 µm and pitch = 150  ±  2 µm) are formed. The optical films are used for diffusion to improve light uniformity of a printed lighting film that consists of lighting stripes and dark blank lines. The evaluation results show that the non-uniformity of light intensity can be reduced from 30% (with only lighting panel) to about 3% with the cylindrical lens films.

  1. Role of large-scale slip in mode II fracture of bimaterial interface produced by diffusion bonding

    NASA Astrophysics Data System (ADS)

    Fox, M. R.; Ghosh, A. K.

    2001-08-01

    Bimaterial interfaces present in diffusion-bonded (and in-situ) composites are often not flat interfaces. The unevenness of the interface can result not only from interface reaction products but also from long-range waviness associated with the surfaces of the component phases bonded together. Experimental studies aimed at determining interface mechanical properties generally ignore the departure in the local stress due to waviness and assume a theoretically flat interface. Furthermore, the commonly used testing methods involving superimposed tension often renders the interface so extremely brittle that if microplastic effects were present it becomes impossible to perceive them. This article examines the role of waviness of the interface and microplastic effects on crack initiation. To do this, a test was selected that provides significant stability against crack growth by superimposing compressive stresses. Mode II interface fracture was studied for NiAl/Mo model laminates using a recently developed asymmetrically loaded shear (ALS) interface shear test. The ALS test may be viewed as opposite of the laminate bend test. In the bend test, shear at the interface is created via tension on one surface of the bend, while in the ALS test, shear is created by compression on one side of the interface relative to the other. Normal to the interface, near the crack tip, an initially compressive state is replaced by slight tension due to Poisson’s expansion of the unbonded part of the compressed beam.

  2. Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)

    PubMed Central

    Peñalver, Francisco-Javier; Sancho, Juan-Manuel; de la Fuente, Adolfo; Olave, María-Teresa; Martín, Alejandro; Panizo, Carlos; Pérez, Elena; Salar, Antonio; Orfao, Alberto

    2017-01-01

    Diffuse large B-cell lymphoma patients have a 5% overall risk of central nervous system events (relapse or progression), which account for high morbidity and frequently fatal outcomes,1 and shortened overall survival of <6 months.2 Early diagnosis of central nervous system events is critical for successful treatment and improved prognosis. Identification of patients at risk of central nervous system disease is critical to accurately identify candidates for central nervous system prophylaxis vs. therapy.3–5 This report by the Spanish Lymphoma Group (GELTAMO) aims to provide useful guidelines and recommendations for the prevention, diagnosis, and treatment of central nervous system diffuse large B-cell lymphoma patients with, or at risk of, leptomeningeal and/or brain parenchyma lymphoma relapse. A panel of lymphoma experts working on behalf of GELTAMO reviewed all data published on these topics available in PubMed up to May 2016. Recommendations were classified according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach.6 A practical algorithm based on the proposed recommendations was then developed (Figure 1). Initial discussions among experts were held in May 2014, and final consensus was reached in June 2016. The final manuscript was reviewed by all authors and the Scientific Committee of GELTAMO. PMID:27846613

  3. Diffuse large B-cell lymphoma in colon confounded by prior history of colorectal cancer: A case report and literature review.

    PubMed

    Ren, Yanling; Chen, Zhilu; Su, Chuanyong; Tong, Hongyan; Qian, Wenbin

    2016-02-01

    A 66-year-old male underwent left hemicolectomy for rectal adenocarcinoma in 2008. Five years later he was admitted to hospital with abdominal pain. A computed tomography scan revealed notable thickening of the middle of the ascending colon wall, and colonoscopy revealed an ulcerofungating mass of 3×3 cm in the cecum and extending to the ascending colon. Under the consideration of cancer recurrence, laparoscopic right hemicolectomy was performed directly. Surgical specimens revealed sheets of large pleomorphic lymphoid cells with nuclei of different sizes, nucleoli and mitotic phases visible in most cells. These tested positive for CD45, CD20 and CD79a diffusely, but negative for CD3, CD5, Bcl-2, Bcl-6 and ALK. The Ki-67 proliferation index was 40%. Epstein-Barr virus in situ hybridization did not reveal any positive signals in any of the tumor cells. Based on these findings, the recurrent tumor was diagnosed as diffuse large B-cell lymphoma. The patient could have avoided surgery and received chemotherapy only; however, the case was confounded by the patient's prior history of colorectal cancer due to the rarity of colon lymphoma following rectal cancer in the same patient. It is therefore essential to investigate carefully and differentiate between potential lesions during routine postoperative colonoscopy following colorectal cancer surgery, as patients may present with rare colon lymphoma, which may be confused with a recurrence of colorectal cancer.

  4. Low-Dose PET/CT and Full-Dose Contrast-Enhanced CT at the Initial Staging of Localized Diffuse Large B-Cell Lymphomas

    PubMed Central

    Sabaté-Llobera, Aida; Cortés-Romera, Montserrat; Mercadal, Santiago; Hernández-Gañán, Javier; Pomares, Helena; González-Barca, Eva; Gámez-Cenzano, Cristina

    2016-01-01

    Computed tomography (CT) has been used as the reference imaging technique for the initial staging of diffuse large B-cell lymphoma until recent days, when the introduction of positron emission tomography (PET)/CT imaging as a hybrid technique has become of routine use. However, the performance of both examinations is still common. The aim of this work was to compare the findings between low-dose 2-deoxy-2-(18F)fluoro-d-glucose (18F-FDG) PET/CT and full-dose contrast-enhanced CT (ceCT) in 28 patients with localized diffuse large B-cell lymphoma according to PET/CT findings, in order to avoid the performance of ceCT. For each technique, a comparison in the number of nodal and extranodal involved regions was performed. PET/CT showed more lesions than ceCT in both nodal (41 vs. 36) and extranodal localizations (16 vs. 15). Disease staging according to both techniques was concordant in 22 patients (79%) and discordant in 6 patients (21%), changing treatment management in 3 patients (11%). PET/CT determined a better staging and therapeutic approach, making the performance of an additional ceCT unnecessary. PMID:27559300

  5. STAT3 activation is associated with cerebrospinal fluid interleukin-10 (IL-10) in primary central nervous system diffuse large B cell lymphoma.

    PubMed

    Mizowaki, Takashi; Sasayama, Takashi; Tanaka, Kazuhiro; Mizukawa, Katsu; Takata, Kumi; Nakamizo, Satoshi; Tanaka, Hirotomo; Nagashima, Hiroaki; Nishihara, Masamitsu; Hirose, Takanori; Itoh, Tomoo; Kohmura, Eiji

    2015-09-01

    Signal transducers and activators of transcription 3 (STAT3) are activated by various cytokines and oncogenes; however, the activity and pathogenesis of STAT3 in diffuse large B cell lymphoma of the central nervous system have not been thoroughly elucidated. We investigated the phosphorylation levels of STAT3 in 40 specimens of primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) and analyzed the association between phsopho-STAT3 (pSTAT3) expression and cerebrospinal fluid (CSF) concentration of interleukin-10 (IL-10) or IL-6. Immunohistochemistry and Western blot analysis revealed that most of the specimens in PCNS DLBCL expressed pSTST3 protein, and a strong phosphorylation levels of STAT3 was statistically associated with high CSF IL-10 levels, but not with CSF IL-6 levels. Next, we demonstrated that recombinant IL-10 and CSF containing IL-10 induced the phosphorylation of STAT3 in PCNS DLBCL cells. Furthermore, molecular subtype classified by Hans' algorithm was correlated with pSTAT3 expression levels and CSF IL-10 levels. These results suggest that the STAT3 activity is correlated with CSF IL-10 level, which is a useful marker for STAT3 activity in PCNS DLBCLs.

  6. [Primary diffuse large B-cell lymphoma of the uterine cervix successfully treated with rituximabplus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy-a case report].

    PubMed

    Hashimoto, Akari; Fujimi, Akihito; Kanisawa, Yuji; Matsuno, Teppei; Okuda, Toshinori; Minami, Shinya; Doi, Tadashi; Ishikawa, Kazuma; Uemura, Naoki; Jyomen, Yuko; Tomaru, Utano

    2013-12-01

    Primary malignant lymphoma of the uterine cervix is a rare disease, and the therapeutic strategy has not been clearly established. A 45-year old woman presented with vaginal bleeding and hypermenorrhea in January 2012. Physical examination revealed a mass in the pelvic cavity approximately the size of a neonate's head. Pelvic magnetic resonance imaging(MRI) showed a solid mass 11 cm in size in the uterine cervix with homogeneous low intensity on T1-weighted images, iso-high intensity on T2-weighted images, and heterogeneous iso-high intensity on gadolinium-diethylenetriaminepentaacetate(Gd- DTPA)-enhanced images. Multiple lymphadenopathy were also detected in the pelvis. The Papanicolaou smear indicated class 5 cervical cytology, and a subsequent histological examination by a punch biopsy of the cervix showed diffuse infiltration of medium- to large-sized mononuclear cells that stained positive for CD20 and CD79a and negative for CD3, CD5, and EBER. Bone marrow biopsy revealed no abnormality. Positron emission tomography-computed tomography(PET-CT)showed strong fluorodeoxyglucose(FDG)accumulation in the uterine cervix mass, and in the pelvic and right inguinal lymphadenopathy. The patient was diagnosed with diffuse large B-cell lymphoma of the uterine cervix, Ann Arbor stage II AE. She was successfully treated with 8 courses of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone(R-CHOP) chemotherapy, and maintains a complete remission.

  7. Synchronous bilateral non-Hodgkin’s diffuse large B-cell lymphoma of the breast and left breast invasive ductal carcinoma: a case report and review of literature

    PubMed Central

    Liu, Weihua; Zhu, Hong; Zhou, Xiaoge

    2014-01-01

    Lymphoma of the breast is unusual, and synchronous bilateral lymphoma and carcinoma of the breast is extremely rare. We present the case of a 51-year-old woman who found a mass in her left breast. Ultrasound scan findings revealed nodules at the 2 o’clock position in her left breast and focal dilation of the duct at the 8-9 o’clock and 10 o’clock position in her right and left breasts, respectively. A left breast ultrasound-guided core needle biopsy and right breast segmental excisional biopsy were performed. Pathological and immunohistochemical examination revealed left breast invasive ductal carcinoma and right breast diffuse large B-cell lymphoma of the non-germinal center type. Pathological examination of the left breast modified radical mastectomy specimen revealed synchronous invasive ductal carcinoma (grade III) and diffuse large B-cell lymphoma. The patient received chemotherapy and bone marrow transplantation in another hospital. Based on a review of the relevant literature, we discuss the diagnosis, clinical features, treatment, and prognosis of synchronous breast lymphoma and invasive ductal carcinoma. PMID:25400793

  8. Imaging by ¹⁸F-FDG PET/CT of diffuse large B-cell lymphoma with cellulitis.

    PubMed

    Zhang, Yiqiu; Li, Beilei; Cai, Liang; Shi, Hongcheng; Hou, Jun

    2015-01-01

    Non-Hodgkin's lymphomas (NHL) quite often present in the neck but are seldom accompanied with cellulitis at the first diagnosis of the disease. We report a 56 year old woman with gradually neck swelling, which was initially treated as cellulitis. After examined by ultrasonography, computed tomography and after pathologically assessments, the diagnosis of large B-cell lymphoma was made. This case highlights the usefulness of fluorine-18-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET/CT) in staging and assessing treatment response in NHL.

  9. HIV/AIDS-related knowledge and behaviors among rural married migrant women in Shandong Province, China: a comparison study.

    PubMed

    Song, Yapei; Kang, Dianmin; Wang, Guoyong; Wei, Chongyi; Tao, Xiaorun; Huang, Tao; Qian, Yuesheng; Zhu, Tiwen; Yang, Shan; Yu, Shaoqi; Wang, Hong; Ma, Wei

    2015-02-01

    Migrant women in China are disproportionately affected by HIV/AIDS. This study described HIV/AIDS-related knowledge and behaviors among married migrant women in Shandong province in comparison to non-migrant local women and identified factors associated with HIV testing history and extramarital sex among married migrant women. A probability-based sample of 1,076 migrant and 1,195 local women were included in the analyses. Compared to local women, married migrant women had lower levels of HIV/AIDS knowledge and were more likely to have had premarital sex, extramarital sex, history of sexually transmitted diseases, and drug use. Less than a quarter of migrant women used condoms consistently in extramarital sex. Only 31.0 % of married migrant women had ever tested for HIV, and the rate of premarital HIV testing was very low. Multivariable analysis showed that married migrant women with a history of extramarital sex were more likely to be from Yunnan province, be living in Yantai city, be in their first marriage, have lower family income, have poor relationship with spouses, use drug, have a history of sexually transmitted diseases, and have lower social support. Our findings provide further evidence that married migrant women are at higher risk for HIV infection and that targeted interventions need to be developed for this population.

  10. Derivation of a Large Isotopic Diffuse Sky Emission Component at 1.25 and 2.2um from the COBE/DIRBE Data

    NASA Astrophysics Data System (ADS)

    Sano, K.; Kawara, K.; Matsuura, S.; Kataza, H.; Arai, T.; Matsuoka, Y.

    2015-10-01

    Using all-sky maps obtained with COBE/DIRBE, we reanalyzed the diffuse sky brightness at 1.25 and 2.2 μ {{m}}, which consists of zodiacal light, diffuse Galactic light (DGL), integrated starlight (ISL), and isotropic emission including the extragalactic background light. Our new analysis including an improved estimate of the DGL and the ISL with the 2MASS data showed that deviations of the isotropic emission from isotropy were less than 10% in the entire sky at high Galactic latitude (| b| \\gt 35^\\circ ). We derived the DGL to 100 μm brightness ratios of ˜4.79 and ˜1.49 n W m-2 MJy-1 at 1.25 and 2.2 μm, respectively. The result of our analysis revealed a significantly large isotropic component at 1.25 and 2.2 μ {{m}} with intensities of 60.15 ± 16.14 and 27.68+/- 6.21 {{n}} {{W}} {{{m}}}-2 {{sr}}-1, respectively. This intensity is larger than the integrated galaxy light, upper limits from γ-ray observation, and potential contribution from exotic sources (i.e., Population III stars, intrahalo light, direct collapse black holes, and dark stars). We therefore conclude that the excess light may originate from the local universe: the Milky Way and/or the solar system.

  11. Involved Field Radiation After Autologous Stem Cell Transplant for Diffuse Large B-Cell Lymphoma in the Rituximab Era

    SciTech Connect

    Biswas, Tithi; Dhakal, Sughosh; Chen Rui; Hyrien, Ollivier; Bernstein, Steven; Friedberg, Jonathan W.; Fisher, Richard I.; Liesveld, Jane; Phillips, Gordon; Constine, Louis S.

    2010-05-01

    Purpose: For patients with recurrent or refractory large B-cell non-Hodgkin's lymphoma, high-dose chemotherapy and autologous stem cell transplant (ASCT) is the treatment of choice. We evaluated the role of involved field radiation therapy (IFRT) post-ASCT for patients initially induced with cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) or, more recently, rituximab-CHOP (R-CHOP). Materials and Methods: Between May 1992 and April 2005, 176 patients underwent ASCT for recurrent or refractory large B-cell non-Hodgkin's lymphoma; 164 patients were evaluable for endpoint analysis. Fifty percent of the CHOP group (n = 131), and 39% of the R-CHOP group (n = 33), received IFRT. Follow-up from the time of transplant was a median/mean of 1.7/3 years (range, 0.03-13 years). Results: The 5-year overall survival (OS) and disease-specific survival (DSS) improved with IFRT in both the R-CHOP (p = 0.006 and 0.02, respectively) and CHOP (p = 0.02 and p = 0.04, respectively) groups. IFRT was associated with a 10% (p = 0.17) reduction in local failure, alone or with a distant site. On univariate analysis, IFRT was associated with superior OS (hazard ratio [HR] = 0.50 [95% CI 0.32, 0.78]; p = 0.002) and DSS (HR = 0.53 [95% CI 0.33, 0.86]; p = 0.009). Presence of B symptoms was adverse (p = 0.03). On multivariate analysis, only IFRT was associated with significant improvement in OS (HR = 0.35 [0.18, 0.68]; p = 0.002) and DSS (HR = 0.39 [95% CI 0.18, 0.84]; p = 0.01). Conclusions: Recognizing that positive and negative patient selection bias exists for the use of IFRT post-ASCT, patients initially treated with CHOP or R-CHOP and who undergo ASCT for recurrent or refractory disease may benefit from subsequent IFRT presumably due to enhanced local control that can translate into a survival advantage.

  12. Cross-Platform Assessment of Genomic Imbalance Confirms the Clinical Relevance of Genomic Complexity and Reveals Loci with Potential Pathogenic Roles in Diffuse Large B-Cell Lymphoma

    PubMed Central

    Dias, Lizalynn M.; Thodima, Venkata; Friedman, Julia; Ma, Charles; Guttapalli, Asha; Mendiratta, Geetu; Siddiqi, Imran N.; Syrbu, Sergei; Chaganti, R. S. K.; Houldsworth, Jane

    2016-01-01

    Genomic copy number alterations (CNAs) in diffuse large B-cell lymphoma (DLBCL) have roles in disease pathogenesis but overall clinical relevance remains unclear. Herein, an unbiased algorithm was uniformly applied across three genome profiling datasets comprising 392 newly-diagnosed DLBCL specimens that defined 32 overlapping CNAs, involving 36 minimal common regions (MCRs). Scoring criteria were established for 50 aberrations within the MCRs while considering peak gains/losses. Application of these criteria to independent datasets revealed novel candidate genes with coordinated expression, such as CNOT2, potentially with pathogenic roles. No one single aberration significantly associated with patient outcome across datasets, but genomic complexity, defined by imbalance in more than one MCR, significantly portended adverse outcome in two of three independent datasets. Thus, the standardized scoring of CNAs currently developed can be uniformly applied across platforms, affording robust validation of genomic imbalance and complexity in DLBCL and overall clinical utility as biomarkers of patient outcome. PMID:26294112

  13. An Unusual Case of Extranodal Diffuse Large B-Cell Lymphoma Infiltrating Skeletal Muscle: A Case Report and Review of the Literature

    PubMed Central

    Hatem, Joseph; Bogusz, Agata M.

    2016-01-01

    Diffuse large B-cell lymphoma is extranodal in approximately 40% of cases, arising in nearly any organ system. DLBCL involvement of soft tissue and in particular skeletal muscle is extremely rare, comprising less than 1% of all extranodal non-Hodgkin lymphomas (NHL). We report a case of a 79-year-old man that presented with a DLBCL of the left triceps. In particular, we describe an unusual histologic appearance of pseudoglandular structures, resembling adenocarcinoma. We performed a review of lymphoma cases involving skeletal muscle diagnosed at our institution over the past 15 years as well as thorough PubMed review of the literature. We discuss the features of lymphoma involving skeletal muscle as it pertains to clinical characteristics, histologic subtype, tumor localization, diagnostic studies, therapy, and outcome. Finally, we highlight the diagnostic difficulties that can present in these rare and often challenging cases. PMID:27247818

  14. A B-cell lymphoma case that is unclassifiable, and intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma of lacrimal gland

    PubMed Central

    Yunoki, Tatsuya; Murakami, Jun; Imagawa, Yukihiro; Nakajima, Takahiko; Hayashi, Atsushi

    2017-01-01

    A 60-year-old woman presented with acute eyelid swelling and a subcutaneous hemorrhage in the right eye. Magnetic resonance imaging showed a spherical tumor of the lacrimal gland. The tumor was removed by the Kroenlein method. We diagnosed as a B-cell lymphoma that is unclassifiable, and intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) (intermediate DLBCL/BL) based on its immunohistopathological examination and c-MYC/IgH rearrangement. We administered six cycles of dose-adjusted-EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride, and rituximab) therapy, and remission of the lymphoma was obtained. This is the first case of an intermediate DLBCL/BL of a lacrimal gland. PMID:28203109

  15. Synchronous Occurrence of Diffuse Large B-cell Lymphoma of the Duodenum and Gastrointestinal Stromal Tumor of the Ileum in a Patient with Immune Thrombocytopenic Purpura

    PubMed Central

    Takahashi, Tohru; Maruyama, Yumiko; Saitoh, Mayuko; Itoh, Hideto; Yoshimoto, Mitsuru; Tsujisaki, Masayuki; Nakayama, Masato

    2016-01-01

    A 64 year-old woman with steroid-dependent immune thrombocytopenia developed anemia. Esophagogastroduodenoscopy revealed the presence of a tumor, which was diagnosed to be diffuse large B-cell lymphoma, in the second portion of the duodenum. 18F-fluorodeoxy glucose positron emission tomography showed an increased uptake mass in the pelvic cavity as well as in the duodenum. Though the duodenal tumor disappeared after 4 cycles of chemotherapy, the pelvic mass did not shrink in size. As a result, laparoscopic resection of the pelvic tumor was performed and the tumor was histologically diagnosed to be a gastrointestinal stromal tumor. Subsequently, the patient was treated with 2 more cycles of the chemotherapy. Eventually, thrombocytopenia completely resolved. PMID:27746431

  16. A 92-year-old man with primary cutaneous diffuse large B-cell non-Hodgkin's lymphoma manifesting as a giant scalp mass

    PubMed Central

    Liao, Chenlong; Yang, Min; Liu, Pengfei; Zhang, Wenchuan

    2017-01-01

    Abstract Rationale: Primary cutaneous non-Hodgkin's lymphoma (NHL) is an uncommon entity, representing 10% of all extranodal NHLs. Among all cutaneous sites, the scalp is a rare site of representation. Patient concerns: A 92-year-old Chinese man visited our hospital with a multiple-nodular huge scalp mass on the right parieto-occipital regions. The mass was of 7-month duration and progressively enlarging in size. Diagnoses: On the basis of the result of biopsy, diffuse large B-cell NHL was diagnosed. Interventions: The mass was partially resected by surgery and no further treatment was conducted due to the advanced age and poor physical status. Outcomes: The tumor relapsed in situ after 6 months and the patient died after 2 years. Lessons: This case highlighted the limited access to standard treatment options in patients with advanced age. A thorough examination is necessary to decide upon the treatment for the primary cutaneous lymphoma. PMID:28272240

  17. The effect of biological heterogeneity on R-CHOP treatment outcome in diffuse large B-cell lymphoma across five international regions.

    PubMed

    Carr, Robert; Ozdag, Hilal; Tekin, Nilgun; Morris, Timothy; Conget, Paulette; Bruna, Flavia; Timar, Botond; Gagyi, Eva; Basak, Ranjan; Naik, Omkar; Auewarakul, Chirayu; Srithana, Narongrit; Dimamay, Mark Pierre; Natividad, Filipinas; Chung, June-Key; Belder, Nevin; Kuzu, Isinsu; Omidvar, Nader; Paez, Diana; Padua, Rose Ann

    2017-05-01

    Addressing the global burden of cancer, understanding its diverse biology, and promoting appropriate prevention and treatment strategies around the world has become a priority for the United Nations and International Atomic Energy Agency (IAEA), the WHO, and International Agency for Research on Cancer (IARC). The IAEA sponsored an international prospective cohort study to better understand biology, treatment response, and outcomes of diffuse large B-cell lymphoma (DLBCL) in low and middle-income countries across five UN-defined geographical regions. We report an analysis of biological variation in DLBCL across seven ethnic and environmentally diverse populations. In this cohort of 136 patients treated to a common protocol, we demonstrate significant biological differences between countries, characterized by a validated prognostic gene expression score (p < .0001), but International Prognostic Index (IPI)-adjusted survivals in all participating countries were similar. We conclude that DLBCL treatment outcomes in these populations can be benchmarked to international standards, despite biological heterogeneity.

  18. A phase II study of sorafenib (BAY 43–9006) in recurrent diffuse large B cell lymphoma: an eastern cooperative oncology group study (E1404)

    PubMed Central

    2013-01-01

    Patients with diffuse large B cell lymphoma (DLBCL) who are not candidates for or recur after autologous stem cell transplant have a poor overall prognosis. We conducted a phase II study of sorafenib (formerly BAY 43–9006) in the treatment of relapsed DLBCL. Fourteen patients were enrolled and assessed for response. Median number of cycles administered was 3 (range, 1–12). Common grade 3 toxicities included fatigue (29%), rash/desquamation (21%) and diarrhea (14%). One complete response (CR) was observed (the 14th patient enrolled). Response rate was 7% (90% CI, 0.4 – 30%). Duration of response was 6 months. Median progression-free survival (PFS) was 2 months (90% CI, 1 – 5 months). Median overall survival (OS) was 9 months (90% CI, 5 – 16 months). Although sorafenib has demonstrated activity in solid malignancies it demonstrated low single agent activity in treatment of DLBCL. PMID:23829878

  19. Diffuse interface modeling of three-phase contact line dynamics on curved boundaries: A lattice Boltzmann model for large density and viscosity ratios

    NASA Astrophysics Data System (ADS)

    Fakhari, Abbas; Bolster, Diogo

    2017-04-01

    We introduce a simple and efficient lattice Boltzmann method for immiscible multiphase flows, capable of handling large density and viscosity contrasts. The model is based on a diffuse-interface phase-field approach. Within this context we propose a new algorithm for specifying the three-phase contact angle on curved boundaries within the framework of structured Cartesian grids. The proposed method has superior computational accuracy compared with the common approach of approximating curved boundaries with stair cases. We test the model by applying it to four benchmark problems: (i) wetting and dewetting of a droplet on a flat surface and (ii) on a cylindrical surface, (iii) multiphase flow past a circular cylinder at an intermediate Reynolds number, and (iv) a droplet falling on hydrophilic and superhydrophobic circular cylinders under differing conditions. Where available, our results show good agreement with analytical solutions and/or existing experimental data, highlighting strengths of this new approach.

  20. Diffuse large B-cell non-Hodgkin lymphoma involving the unilateral carotid space in an elderly man: A case report

    PubMed Central

    Chen, Bo; Zou, Chunying; Wu, Jianqing

    2017-01-01

    An 84-year-old man presented with a history of repeated syncope and decreased heart rate and blood pressure over the last month. On physical examination, a mass sized ~3×3 cm was palpable in the left submandibular area; the mass was hard, poorly mobile, without tenderness or local skin irritation. The computed tomography angiography examination revealed a soft tissue mass in the neck, at the level of the left carotid bifurcation and above. The left common carotid artery bifurcation and internal and external carotid artery segment were embedded in the mass, and there were multiple enlarged lymph nodes in the left neck. The diagnosis of diffuse large B-cell non-Hodgkin lymphoma was confirmed by a percutaneous biopsy of the left submandibular mass. To the best of our knowledge, this is the first reported case of non-Hodgkin lymphoma involvign the carotid space. PMID:28123742

  1. The Explorer of Diffuse Galactic Emission (EDGE): Determination of Large-Scale Structure Evolution from Measurement of the Anisotropy of the Cosmic Infrared Background

    NASA Technical Reports Server (NTRS)

    Silverberg, R. F.; Cheng, E. S.; Cottingham, D. A.; Fixsen, D. J.; Meyer, S. S.; Wilson, G. W.

    2004-01-01

    The formation of the first objects, stars and galaxies and their subsequent evolution remain a cosmological unknown. Few observational probes of these processes exist. The Cosmic Infrared Background (CIB) originates from this era, and can provide information to test models of both galaxy evolution and the growth of primordial structure. The Explorer of Diffuse Galactic Emission (EDGE) is a proposed balloon-borne mission designed to measure the spatial fluctuations in the CIB from 200 micrometers to 1 millimeter on 6' to 3 degree scales with 2 microKelvin sensitivity/resolution element. Such measurements would provide a sensitive probe of the large-scale variation in protogalaxy density at redshifts approximately 0.5-3. In this paper, we present the scientific justification for the mission and show a concept for the instrument and observations.

  2. Unusual Presentation of Epstein-Barr Virus-Positive Diffuse Large B-Cell Non-Hodgkin Lymphoma of the Elderly.

    PubMed

    Hong, Bosun; Petrosyan, Vahe; Kruger, Anton R

    2016-06-01

    This report describes the case of a 76-year-old woman diagnosed with Epstein-Barr virus-positive diffuse large B-cell non-Hodgkin lymphoma of the elderly. She had an unusual presentation of the disease with widespread skeletal muscle, masticatory muscle, and parotid gland involvement and the development of interesting erythematous lesions in the neck during chemotherapy. One month after completion of chemotherapy, positron-emission tomography (PET) showed features of persistent lymphoma, but a repeat PET scan a month later showed no active disease. This case reiterates 2 important points: first, to consider lymphoma a differential diagnosis in masticatory muscle enlargement and second, to question false positivity when interpreting post-treatment PET scan results, especially in the absence of clinical disease.

  3. Diffuse large B-cell lymphoma associated with the use of biologic and other investigational agents: the importance of long-term post-marketing safety surveillance.

    PubMed

    Goddard, Allison; Borovicka, Judy H; West, Dennis P; Evens, Andrew M; Laumann, Anne

    2011-01-01

    This case report describes a patient who developed diffuse large B-cell lymphoma (DLBCL) after receiving courses of two investigational biologic agents and cyclosporine followed by more than four years of subcutaneous efalizumab for the treatment of extensive chronic plaque psoriasis. Three years later, the patient remains free of lymphoma and his psoriasis is well controlled with thrice-weekly narrow-band ultraviolet phototherapy. This case emphasizes the importance of continued long-term post-marketing safety surveillance and the early reporting of all possible serious side effects, including cancers, related to the use of any newly available product. In particular, surveillance should focus on the immunomodulating biologic agents in order to identify possible dangerous sequelae.

  4. Randomized Trial Comparing R-CHOP Versus High-Dose Sequential Chemotherapy in High-Risk Patients With Diffuse Large B-Cell Lymphomas.

    PubMed

    Cortelazzo, Sergio; Tarella, Corrado; Gianni, Alessandro Massimo; Ladetto, Marco; Barbui, Anna Maria; Rossi, Andrea; Gritti, Giuseppe; Corradini, Paolo; Di Nicola, Massimo; Patti, Caterina; Mulé, Antonino; Zanni, Manuela; Zoli, Valerio; Billio, Atto; Piccin, Andrea; Negri, Giovanni; Castellino, Claudia; Di Raimondo, Francesco; Ferreri, Andrés J M; Benedetti, Fabio; La Nasa, Giorgio; Gini, Guido; Trentin, Livio; Frezzato, Maurizio; Flenghi, Leonardo; Falorio, Simona; Chilosi, Marco; Bruna, Riccardo; Tabanelli, Valentina; Pileri, Stefano; Masciulli, Arianna; Delaini, Federica; Boschini, Cristina; Rambaldi, Alessandro

    2016-11-20

    Purpose The benefit of high-dose chemotherapy with autologous stem-cell transplantation (ASCT) as first-line treatment in patients with diffuse large B-cell lymphomas is still a matter of debate. To address this point, we designed a randomized phase III trial to compare rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-14 (eight cycles) with rituximab plus high-dose sequential chemotherapy (R-HDS) with ASCT. Patients and Methods From June 2005 to June 2011, 246 high-risk patients with a high-intermediate (56%) or high (44%) International Prognostic Index score were randomly assigned to the R-CHOP or R-HDS arm, and 235 were analyzed by intent to treat. The primary efficacy end point of the study was 3-year event-free survival, and results were analyzed on an intent-to-treat basis. Results Clinical response (complete response, 78% v 76%; partial response, 5% v 9%) and failures (no response, 15% v 11%; and early treatment-related mortality, 2% v 3%) were similar after R-CHOP versus R-HDS, respectively. After a median follow-up of 5 years, the 3-year event-free survival was 62% versus 65% ( P = .83). At 3 years, compared with the R-CHOP arm, the R-HDS arm had better disease-free survival (79% v 91%, respectively; P = .034), but this subsequently vanished because of late-occurring treatment-related deaths. No difference was detected in terms of progression-free survival (65% v 75%, respectively; P = .12), or overall survival (74% v 77%, respectively; P = .64). Significantly higher hematologic toxicity ( P < .001) and more infectious complications ( P < .001) were observed in the R-HDS arm. Conclusion In this study, front-line intensive R-HDS chemotherapy with ASCT did not improve the outcome of high-risk patients with diffuse large B-cell lymphomas.

  5. Infundibulo-hypophysitis-like radiological image in a patient with pituitary infiltration of a diffuse large B-cell non-Hodgkin lymphoma

    PubMed Central

    León-Suárez, A; Roldán-Sarmiento, P; Gómez-Sámano, M A; Nava-De la Vega, A; Enríquez-Estrada, V M; Gómez-Pérez, F J

    2016-01-01

    Summary Non-Hodgkin lymphoma (NHL) is a hematological tumor caused by abnormal lymphoid proliferation. NHL can arise in any part of the body, including central nervous system (CNS). However, pituitary involvement is a quite rare presentation. The diffuse large B-cell lymphoma (DLBCL) is the most common subtype when pituitary is infiltrated. Here, we report a case of pituitary infiltration of NHL DLBCL type in a woman with hypopituitarism and an infundibulum-hypophysitis-like image on magnetic resonance imaging (MRI). A female aged 64 years, complained of dyspepsia, fatigue, weight loss and urine volume increment with thirst. Endoscopy and gastric biopsy confirmed diffuse large B-cell lymphoma. Treatment with chemotherapy using R-CHOP was initiated. During her hospitalization, hypotension and polyuria were confirmed. Hormonal evaluation was compatible with central diabetes insipidus and hypopituitarism. Simple T1 sequence of MRI showed thickening of the infundibular stalk with homogeneous enhancement. After lumbar puncture analysis, CNS infiltration was confirmed showing positive atypical lymphocytes. Pituitary and infundibular stalk size normalized after R-CHOP chemotherapy treatment. In conclusion, pituitary infiltration of NHL with infundibular-hypophysitis-like image on MRI is a rare finding. Clinical picture included hypopituitarism and central diabetes insipidus. Diagnosis should be suspected after biochemical analysis and MRI results. Treatment consists of chemotherapy against NHL and hormonal replacement for pituitary dysfunction. Learning points: Pituitary infiltration by lymphoma can present with signs and symptoms of panhypopituitarism and diabetes insipidus. MRI findings can resemble an autoimmune hypophysitis. Patients can recover pituitary function as well as normalization of MRI after chemotherapy treatment. PMID:28035285

  6. The impact of changes in parameterizations of surface drag and vertical diffusion on the large-scale circulation in the Community Atmosphere Model (CAM5)

    NASA Astrophysics Data System (ADS)

    Lu, Feiyu; Liu, Zhengyu; Liu, Yun; Zhang, Shaoqing; Jacob, Robert

    2016-08-01

    Simulations with the Community Atmosphere Model version 5 (CAM5) are used to analyze the sensitivity of the large-scale circulation to changes in parameterizations of orographic surface drag and vertical diffusion. Many GCMs and NWP models use enhanced turbulent mixing in stable conditions to improve simulations, while CAM5 cuts off all turbulence at high stabilities and instead employs a strong orographic surface stress parameterization, known as turbulent mountain stress (TMS). TMS completely dominates the surface stress over land and reduces the near-surface wind speeds compared to simulations without TMS. It is found that TMS is generally beneficial for the large-scale circulation as it improves zonal wind speeds, Arctic sea level pressure and zonal anomalies of the 500-hPa stream function, compared to ERA-Interim. It also alleviates atmospheric blocking frequency biases in the Northern Hemisphere. Using a scheme that instead allows for a modest increase of turbulent diffusion at higher stabilities only in the planetary boundary layer (PBL) appears to in some aspects have a similar, although much smaller, beneficial effect as TMS. Enhanced mixing throughout the atmospheric column, however, degrades the CAM5 simulation. Evaluating the simulations in comparison with detailed measurements at two locations reveals that TMS is detrimental for the PBL at the flat grassland ARM Southern Great Plains site, giving too strong wind turning and too deep PBLs. At the Sodankylä forest site, the effect of TMS is smaller due to the larger local vegetation roughness. At both sites, all simulations substantially overestimate the boundary layer ageostrophic flow.

  7. PD1 and PDL1 expression in primary central nervous system diffuse large B-cell lymphoma are frequent and expression of PD1 predicts poor survival.

    PubMed

    Four, Marion; Cacheux, Valère; Tempier, Ariane; Platero, Dolorès; Fabbro, Michel; Marin, Grégory; Leventoux, Nicolas; Rigau, Valérie; Costes-Martineau, Valérie; Szablewski, Vanessa

    2016-12-13

    Primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is a rare and aggressive type of diffuse large B-cell lymphoma (DLBCL) whit poorly understood pathogenesis. Finding biomarkers associated with patient survival may be important for understanding its physiopathology and to develop new therapeutic approaches. We investigated 32 PCNS-DLBCL from immunocompetent patients for BCL2, CMYC, LMO2, and P53 expression and for cytogenetic aberrations of BCL2, BCL6, and MYC genes, all known for their prognostic value in systemic DLBCL (s-DLBCL). We analyzed PD1 and PDL1 protein expression in both tumor infiltrating lymphocytes (TILs) and tumor cells. Finally, we searched for correlation between biological data and clinical course. The PCNS-DLBCL expressed BCL2, CMYC, LMO2, and P53 at similar frequency than s-DLBCL but without significant prognostic on survival. None cases harbored aberrations involving BCL2 and MYC gene whereas BCL6 abnormalities were present in 20.7% of cases but without value on survival. Expression of PD1 in TILs and PDL1 in tumor cells was observed at higher rates than in s-DLBCL (58% and 37%, respectively). The PD1 expression in TILs correlated with PDL1 expression in tumor cells (P = .001). Presence of PD1 positive TILs was associated with poorer overall survival (P = .011). Patients with PDL1 overexpression tended to better response to chemotherapy (P = .23). In conclusion PCNS-DLBCL pathogenesis differs from s-DLBCL without prognostic value of the phenotypic and cytogenetic parameters known for their pejorative impact in the latter. The PD1/PDL1 pathway plays a strong role in PCNS-DLBCL and represents an attractive target for this aggressive lymphoma.

  8. PD-1 Blockade Can Restore Functions of T-Cells in Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma In Vitro.

    PubMed

    Quan, Lina; Chen, Xue; Liu, Aichun; Zhang, Yan; Guo, Xiuchen; Yan, Shujie; Liu, Yue

    2015-01-01

    Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV+DLBCL) is an aggressive malignancy that is largely resistant to current therapeutic regimens, and is an attractive target for immune-based therapies. Anti-programmed death-1 (PD-1) antibodies showed encouraging anti-tumor effects in both preclinical models and advanced solid and hematological malignancies, but its efficacy against EBV+DLBCL is unknown. Herein, we performed experiments using co-culture system with T cells and lymphoma cell lines including EBV+DLBCL and EBV-DLBCL [including germinal center B-cell like (GCB)-DLBCL and non-GCB-DLBCL] in vitro. We show that lymphoma cells augmented the expression of PD-1 on T cells, decreased the proliferation of T cells, and altered the secretion of multiple cytokines. However, through PD-1 blockade, these functions could be largely restored. Notbaly, the effect of PD-1 blockade on antitumor immunity was more effective in EBV+DLBCL than that in EBV-DLBCL in vitro. These results suggest that T-cell exhaustion and immune escape in microenvironment is one of the mechanisms underlying DLBCL; and PD-1 blockade could present as a efficacious immunotherapeutic treatment for EBV+DLBCL.

  9. Longitudinal Effects of Coping on Outcome in a Randomized Controlled Trial of a Group Intervention for HIV-Positive Adults with AIDS-Related Bereavement

    ERIC Educational Resources Information Center

    Hansen, Nathan B.; Tarakeshwar, Nalini; Ghebremichael, Musie; Zhang, Heping; Kochman, Arlene; Sikkema, Kathleen J.

    2006-01-01

    This study examined the longitudinal effects of coping on outcome one year following completion of a randomized, controlled trial of a group coping intervention for AIDS-related bereavement. Bereaved HIV-positive participants (N = 267) were administered measures of grief, psychiatric distress, quality of life, and coping at baseline,…

  10. The Unfinished Nature of Rights-Informed HIV- and AIDS-Related Education: An Analysis of Three School-Based Initiatives

    ERIC Educational Resources Information Center

    Miedema, Esther; Maxwell, Claire; Aggleton, Peter

    2015-01-01

    Over the past 25 years, there has been growing investment in concepts of rights in the areas of HIV prevention, care and treatment, including HIV- and AIDS-related education delivered in schools. Despite this increasing commitment to the notion of rights, few efforts appear to have been made to understand the varying conceptions of rights that…

  11. With and With"out": The Bereavement Experiences of Gay Men Who Have Lost a Partner to Non-AIDS-Related Causes

    ERIC Educational Resources Information Center

    Hornjatkevyc, Nina L.; Alderson, Kevin G.

    2011-01-01

    This study gives voice to the experiences of gay men who have lost a partner to non-AIDS-related causes, a subject that has received little attention in the psychological literature. Interviews were conducted with 8 gay men. An analysis informed by hermeneutic phenomenology generated themes and contextualized meanings regarding the participants'…

  12. Efficacy and safety of Stealth liposomal doxorubicin in AIDS-related Kaposi's sarcoma. The International SL-DOX Study Group.

    PubMed Central

    Goebel, F. D.; Goldstein, D.; Goos, M.; Jablonowski, H.; Stewart, J. S.

    1996-01-01

    The utility of current chemotherapeutic regimens in the treatment of AIDS-related Kaposi's sarcoma (AIDS-KS) is often compromised by both limited efficacy and substantial toxicity. Pegylated (Stealth) liposomal doxorubicin hydrochloride (SL-DOX) has been demonstrated specifically to deliver high concentrations of doxorubicin to Kaposi's sarcoma (KS) lesions. This phase II study was performed to evaluate the efficacy and safety of SL-DOX in the treatment of moderate to severe AIDS-KS. Patients were treated biweekly with 10, 20, or 40 mg m-2 SL-DOX. Tumour response was assessed according to AIDS Clinical Trials Groups (ACTG) criteria before each cycle. Best response was determined for 238 patients and was achieved after a mean of 2.3 cycles (range 1-20). Fifteen patients (6.3%) had a complete response to SL-DOX, 177 (74.4%) had a partial response, 44 (18.5%) had stable disease and two (0.8%) had disease progression. SL-DOX was well tolerated: ten patients discontinued therapy because of adverse events, in four cases because of neutropenia. Grade 3 or 4 neutropenia occurred after 281 of 2023 cycles (13.9%) but involved 137 of 240 patients (57.1%) for whom data were available. SL-DOX has substantial activity in AIDS-KS. Best response is typically seen after fewer than three cycles of chemotherapy and in some cases may be prolonged. The most important adverse event is neutropenia, which occurs after a minority of cycles but which may occur in over half of all patients. PMID:8611437

  13. HIV/AIDS-related stigma and discrimination: accounts of HIV-positive Caribbean people in the United Kingdom.

    PubMed

    Anderson, Moji; Elam, Gillian; Gerver, Sarah; Solarin, Ijeoma; Fenton, Kevin; Easterbrook, Philippa

    2008-09-01

    This paper explores the effects of HIV/AIDS-related stigma and discrimination (HASD) on HIV-positive Caribbean people in the Caribbean and the UK. In-depth, semi-structured interviews were held with a purposively selected group of 25 HIV-positive people of Caribbean origin, using primary selection criteria of sex, age, sexuality and country of birth. Interviews with respondents revealed that they are keenly aware of the stigma surrounding HIV/AIDS, which some attribute to a particularly Caribbean combination of fear of contamination, homophobia, and ignorance, reinforced by religious beliefs. In fact, religion serves a double role: underpinning stigma and assisting in coping with HIV. HASD has usually occurred where respondents have lost or do not have control over disclosure. Compared to UK-born respondents, the accounts of Caribbean-born respondents, most of whom were born in Jamaica, include more reports of severe HASD, particularly violence and employment discrimination. All respondents mobilise a variety of strategies in order to avoid HASD, which have implications for their social interactions and emotional well being. While some manage to avoid the "spoiled identity" of the stigmatised, thereby creating their own understandings of HIV infection, these may remain individual-level negotiations. HASD affects HIV-positive Caribbean people at home and in the diaspora in a variety of ways: emotionally, mentally, financially, socially and physically. Interventions specifically addressing stigma and discrimination must be formulated for the UK's Caribbean population. Tackling stigma and discrimination requires more than education; it requires "cultural work" to address deeply entrenched notions of sexuality.

  14. High titer anti-HIV antibody reactivity associated with a paraprotein spike in a homosexual male with AIDS related complex.

    PubMed

    Ng, V L; Hwang, K M; Reyes, G R; Kaplan, L D; Khayam-Bashi, H; Hadley, W K; McGrath, M S

    1988-05-01

    We observed a human immunodeficiency virus (HIV)-infected homosexual male with AIDS related complex (ARC) who had a serum globulin level of 80 g/L. Serum protein electrophoresis revealed a gamma globulin fraction of 40 g/L, of which 50% (20 g/L) was contained within a paraprotein spike, comprised predominantly of IgG kappa. This patient also had high titer anti-HIV antibodies in his serum, which were Western blot reactive at a final dilution of 1:500,000, and recognized gp120env, p66pol, p55gag, p53pol, p41gag, and p24gag. Because paraproteins in the past have been shown to be directed against specific antigens, we purified this patient's paraprotein using a modified high performance liquid chromatography (HPLC)-hydroxylapatite procedure and tested the purified paraprotein for anti-HIV antibody activity. The purified paraprotein retained anti-HIV antibody activity to a final dilution of 1:100,000, and recognized p66pol, p55gag, p53pol, p41gag, and p24gag. The recognition of both "gag" and "pol" gene products suggested that the purified paraprotein might not be monoclonal in origin. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that the purified paraprotein contained at least two immunoglobulin light chain species (Mol wt 30 to 33 Kd). Affinity chromatography of the purified paraprotein using a p24-Sepharose 4B matrix separated the "gag" and "pol" antibody activities. Immunoglobulin gene rearrangement analysis of a bone marrow aspirate (which contained 15% plasma cells) failed to reveal a clonal population of immunoglobulin producing cells. We conclude that this patient's paraprotein accounted for most of the anti-HIV activity present in whole serum, and that this paraprotein was not monoclonal in origin.

  15. Replacement of conventional doxorubicin by pegylated liposomal doxorubicin in standard RCHOP chemotherapy for elderly diffuse large B-Cell lymphoma: a retrospective study in China

    PubMed Central

    Zhou, De; Li, Li; Bao, Changqian; Zhu, Jingjing; Zhu, Lixia; Yang, Xiudi; Zheng, Yanlong; Zhou, Meng; Luo, Xuxia; Xie, Wanzhuo; Ye, Xiujin

    2015-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of non-Hodgkin’s lymphoma (NHL) in adults, and approximately 50% of cases of DLBCL occur in patients above the age of 60. Although RCHOP regimen was established as the standard therapy for DLBCL patients, there are still a large number of DLBCL patients who can’t bear the toxicity of doxorubicin, especially in elderly patients. Pegylated liposomal doxorubicin (PLD) offers a new strategy for elderly DLBCL patients. In our study, we reviewed 103 newly diagnosed patients with DLBCL aged between 60 years to 75 years old who were treated with RCHOP (62 cases) or DRCOP (41 cases) regimen. All the patients completed a mean follow-up period of 28 months (range, 2 to 48 months). There was no statistical difference of OS between the DRCOP (78.0%) and RCHOP (72.6%) groups (P = 0.787). And there were less grade 3-4 cardiotoxicity in patients treated with DRCOP (9.8%) than RCHOP regimen (27.4%, P = 0.029). Our findings in this study indicate that the DRCOP regimen offers similar oncologic efficacy when weighed against the standard RCHOP regimen in elderly DLBCL patients, and it might be a more secure treatment for elderly DLBCL patients who have additional risk factors for cardiac diseases. PMID:26885233

  16. Mass-transport-controlled, large-area, uniform deposition of carbon nanofibers and their application in gas diffusion layers of fuel cells.

    PubMed

    Tang, Xian; Xie, Zhiyong; Huang, Qizhong; Chen, Guofen; Hou, Ming; Yi, Baolian

    2015-05-07

    The effect of mass transport on the growth characteristics of large-area vapor-grown carbon nanofibers (CNFs) was investigated by adjusting the substrate deposition angle (α). The catalyst precursor solution was coated onto one side of a 2D porous carbon paper substrate via a decal printing method. The results showed that the CNFs were grown on only one side of the substrate and α was found to significantly affect the growth uniformity. At α = 0°, the growth thickness, the density, the microstructure and the yield of the CNF film were uniform across the substrate surface, whereas the growth uniformity decreased with increasing α, suggesting that the large-area CNF deposition processes were mass-transport-controlled. Computational fluid dynamics simulations of the gas diffusion processes revealed the homogeneous distributions of the carbon-source-gas concentration, pressure, and velocity near the substrate surface at α = 0°, which were the important factors in achieving the mass-transport-limited uniform CNF growth. The homogeneity of the field distributions decreased with increasing α, in accordance with the variation in the growth uniformity with α. When used as a micro-porous layer, the uniform CNF film enabled higher proton exchange membrane fuel cell performance in comparison with commercial carbon black by virtue of its improved electronic and mass-transport properties confirmed by the electrochemical impedance spectroscopy results.

  17. T-cell-rich B-cell lymphoma: a clinicopathologic study of 21 cases and comparison with 43 cases of diffuse large B-cell lymphoma.

    PubMed

    Aki, Hilal; Tuzuner, Nukhet; Ongoren, Seniz; Baslar, Zafer; Soysal, Teoman; Ferhanoglu, Burhan; Sahinler, Ismet; Aydin, Yildiz; Ulku, Birsen; Aktuglu, Gulten

    2004-03-01

    Clinicopathologic features of 21 patients with T-cell-rich B-cell lymphoma (TCRBCL) were reviewed and compared to 43 patients with diffuse large B-cell lymphoma (DLBCL) to determine if there were distinguishing clinical characteristics and differences in response or survival to CHOP therapy. For the diagnosis of TCRBCL, the current WHO criteria was used. In all of our cases, the majority of cells are non-neoplastic T cells and <10% large neoplastic B cells are present. The initial pathologic diagnosis was nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) in two cases. Patients with TCRBCL were significantly younger (median: 46 years) and had a significantly higher incidence of B symptoms (62%), hepatomegaly (33%) and marrow infiltration (33%) at presentation when compared to DLBCL (P<0.03). The CR rate after treatment was 48% for TCRBCL patients versus 79% for the DLBCL (P<0.003). Although the CR rates in between the two groups are significant, the difference in 3 years survival rates in each CR groups was insignificant (80% versus 77%). The overall survival time in the two groups was 17 months. Event-free survival time in TCRBCL was 12 months, compared with 17 months in the DLBCL (P>0.05). The frequency of patients with TCRBCL achieving CR was 52.6% whereas that of patients with DLBCL was 79% (P<0.003). The TCRBCL 3 years event-free survival 48% and overall survival 64% were 63 and 72% for DLBCL, respectively.

  18. Autograft HIV-DNA load predicts HIV-1 peripheral reservoir after stem cell transplantation for AIDS-related lymphoma patients.

    PubMed

    Zanussi, Stefania; Bortolin, Maria Teresa; Pratesi, Chiara; Tedeschi, Rosamaria; Basaglia, Giancarlo; Abbruzzese, Luciano; Mazzucato, Mario; Spina, Michele; Vaccher, Emanuela; Tirelli, Umberto; Rupolo, Maurizio; Michieli, Mariagrazia; Di Mascio, Michele; De Paoli, Paolo

    2015-01-01

    Autologous stem cell transplantation (ASCT) is a widely used procedure for AIDS-related lymphomas, and it represents an opportunity to evaluate strategies curing HIV-1 infection. The association of autograft HIV-DNA load with peripheral blood HIV-1 reservoir before ASCT and its contribution in predicting HIV-1 reservoir size and stability during combination antiretroviral therapy (cART) after transplantation are unknown. Aiming to obtain information suggesting new functional cure strategies by ASCT, we retrospectively evaluated HIV-DNA load in autograft and in peripheral blood before and after transplantation in 13 cART-treated HIV-1 relapse/refractoring lymphoma patients. Among them seven discontinued cART after autograft infusion. HIV-DNA was evaluated by a sensitive quantitative real-time polymerase chain reaction (PCR). After debulking chemotherapy/mobilization, the autograft HIV-1 reservoir was higher than and not associated with the peripheral HIV-1 reservoir at baseline [median 215 HIV-DNA copies/10(6) autograft mononuclear cells, range 13-706 vs. 82 HIV-DNA copies/10(6) peripheral blood mononuclear cells (PBMCs), range 13-479, p = 0.03]. After high dose chemotherapy and autograft infusion, HIV-DNA levels reached a plateau between month 6 and 12 of follow-up. No association was found between peripheral HIV-DNA levels at baseline and after infusion in both cART interrupting and not interrupting patients. Only in the last subgroup, a stable significant linear association between autograft and peripheral blood HIV-1 reservoir emerged from month 1 (R(2) = 0.84, p = 0.01) to month 12 follow-up (R(2) = 0.99, p = 0.0005). In summary, autograft HIV-1 reservoir size could be influenced by the mobilization phase and predicts posttransplant peripheral HIV-1 reservoir size in patients on continuous cART. These findings could promote new research on strategies reducing the HIV-1 reservoir by using the ASCT procedure.

  19. Copy number gain at 12q12-14 may be important in the transformation from follicular lymphoma to diffuse large B cell lymphoma

    PubMed Central

    Hough, R E; Goepel, J R; Alcock, H E; Hancock, B W; Lorigan, P C; Hammond, D W

    2001-01-01

    The purpose of this study was to identify novel areas of genomic copy number change associated with transformation from follicular lymphoma (FL) to diffuse large B cell lymphoma (DLBL). DNA was extracted from tumour cells micro-dissected from paraffin- embedded tissue sections in 24 patients with FL and subsequent transformation to DLBL and 18 patients with de novo DLBL. Tumour DNA was compared to reference DNA using comparative genomic hybridization. Abnormalities common to all 3 groups were gains on chromosomes 4q, 5q, 7q, 11q and X and losses on 3p, 8p and 10q. Copy number changes seen in both transformed and de novo DLBL and not seen in FL were gains on 2p and losses on 1q, 15q and Xq. Gains on 2q, 6p, 7p and 17q and losses on 5p and 8q were specific to transformed DLBL cases. Gain on 12q12-14 was found in 52% of the transformed DLBL cases and was never seen in its follicular counterpart. Patterns of genomic copy number change associated with specific clinical events in NHL have been demonstrated and suggest that gains on 2q, 6p, 7p, 12q and 17q and losses on 5p and 8q may be important in the transformation from low to high-grade disease. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11207045

  20. Minimal residual disease detection by flow cytometry and PARR in lymph node, peripheral blood and bone marrow, following treatment of dogs with diffuse large B-cell lymphoma.

    PubMed

    Aresu, Luca; Aricò, Arianna; Ferraresso, Serena; Martini, Valeria; Comazzi, Stefano; Riondato, Fulvio; Giantin, Mery; Dacasto, Mauro; Guadagnin, Eleonora; Frayssinet, Patrick; Rouquet, Nicole; Drigo, Michele; Marconato, Laura

    2014-05-01

    The most promising techniques for detecting minimal residual disease (MRD) in canine lymphoma are flow cytometry (FC) and polymerase chain reaction amplification of antigen receptor genes (PARR). However, the agreement between these methods has not been established. MRD was monitored by FC and PARR following treatment of dogs affected with diffuse large B-cell lymphoma (DLBCL), comparing results in lymph node (LN), peripheral blood (PB) and bone marrow (BM) samples. The prognostic impact of MRD on time to relapse (TTR) and lymphoma-specific survival (LSS) was also assessed. Fourteen dogs with previously untreated DLBCL were enrolled into the study; 10 dogs eventually relapsed, while four dogs with undetectable MRD were still in remission at the end of the study. At diagnosis, the concordance rate between FC and PARR was 100%, 78.6%, and 64.3% for LN, PB and BM, respectively. At the end of treatment, the agreement rates were 35.7%, 50%, and 57.1% for LN, PB and BM, respectively. At least one of the follow-up samples from dogs experiencing relapse was PARR(+); conversely, FC was not able to detect MRD in seven of the dogs that relapsed. PARR was more sensitive than FC in predicting TTR, whereas the combination of PARR and FC was more sensitive than either technique alone in predicting LSS using PB samples. The results suggest that immunological and molecular techniques should be used in combination when monitoring for MRD in canine DLBCL.

  1. Nuclear Import of JAK1 Is Mediated by a Classical NLS and Is Required for Survival of Diffuse Large B-cell Lymphoma.

    PubMed

    Zhu, Fen; Hwang, Byounghoon; Miyamoto, Shigeki; Rui, Lixin

    2017-03-01

    JAKs are non-receptor tyrosine kinases that are generally found in association with cytokine receptors. In the canonical pathway, roles of JAKs have well been established in activating STATs in response to cytokine stimulation to modulate gene transcription. In contrast, a noncanonical role of JAK2 has recently been discovered, in which JAK2 in the nucleus imparts the epigenetic regulation of gene transcription through phosphorylation of tyrosine 41 on the histone protein H3. Recent work further demonstrated that this noncanonical mechanism is conserved with JAK1, which is activated by the autocrine cytokines IL6 and IL10 in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), a cancer type that is particularly difficult to treat and has poor prognosis. However, how JAK1 gains access to the nucleus to enable epigenetic regulation remains undefined. Here, we investigated this question and revealed that JAK1 has a classical nuclear localization signal toward the N-terminal region, which can be recognized by multiple importin α isoforms. Moreover, the nuclear import of JAK1 is independent of its kinase activity but is required for the optimal expansion of ABC DLBCL cells in vitroImplications: This study demonstrates that the nuclear import of JAK1 is essential for the optimal fitness of ABC DLBCL cells, and targeting JAK1 nuclear localization is a potential therapeutic strategy for ABC DLBCL. Mol Cancer Res; 15(3); 348-57. ©2016 AACR.

  2. Second-line therapy in diffuse large B-cell lymphoma (DLBCL): treatment patterns and outcomes in older patients receiving outpatient chemotherapy.

    PubMed

    Danese, Mark D; Griffiths, Robert I; Gleeson, Michelle L; Dalvi, Tapashi; Li, Jingyi; Mikhael, Joseph R; Deeter, Robert; Dreyling, Martin

    2017-05-01

    Using SEER-Medicare linked data we identified elderly patients diagnosed with diffuse large B-cell lymphoma (DLBCL) between January 2000 and December 2007 who received second-line outpatient chemotherapy for relapsed or refractory disease. Second-line regimens were classified into three mutually exclusive groups: aggressive, conventional, and palliative. Of the 632 (426 relapsed, 206 refractory) patients in the cohort, 27.8% received aggressive second-line therapy, 39.1% received conventional therapy, and 33.1% received palliative therapy. There were no differences in survival by type of therapy received, either for relapsed or refractory patients, although the patient risk profile differed significantly. However, duration of remission, male gender, and anemia at diagnosis were important predictors in relapsed patients, and male gender, B-symptoms, comorbidity burden, and poverty status were important predictors in refractory patients. Survival in elderly patients receiving second-line therapy remains poor, and the 24-month cost of all care exceeds $97,000. Patients would benefit from improved treatment options.

  3. Detection of prognostic factors in children and adolescents with Burkitt and Diffuse Large B-Cell Lymphoma treated with the AIEOP LNH-97 protocol.

    PubMed

    Pillon, Marta; Mussolin, Lara; Carraro, Elisa; Conter, Valentino; Aricò, Maurizio; Vinti, Luciana; Garaventa, Alberto; Piglione, Matilde; Buffardi, Salvatore; Sala, Alessandra; Santoro, Nicola; Lo Nigro, Luca; Mura, Rossella; Tondo, Annalisa; Casale, Fiorina; Farruggia, Piero; Pierani, Paolo; Cesaro, Simone; d'Amore, Emanuele S G; Basso, Giuseppe

    2016-11-01

    Burkitt lymphoma (BL) and Diffuse Large B-Cell Lymphoma (DLBCL) account for most cases of non-Hodgkin lymphoma (NHL) in childhood. We report the clinical characteristics, outcome and prognostic factors in children with BL or DLBCL treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) LNH-97 protocol. Patients aged up to 18 years that were newly diagnosed with BL/DLBCL were included in the study. Therapy consisted of pre-phase followed by 2-6 high-dose chemotherapy courses tailored according to lactate dehydrogenase (LDH) value and disease stage. A total of 442 patients (379 BL, 63 DLBCL) were enrolled between 1997 and 2014, of whom 18 failed to achieve remission, 6 experienced treatment-related death, 2 developed second malignancy and 20 relapsed. At a median follow-up time of 5 years, overall survival was 93% (±1%) and event-free survival was 90% (±1%). LDH value above the median value had an independently negative prognostic value (P < 0·0001). However, in the subgroup of 128 patients in which minimal disseminated disease (MDD) was analysed, MDD-positivity became the only unfavourable prognostic factor for progression-free survival. Tailored chemotherapy could be extremely effective with limited toxicity. Identification of MDD as a hallmark of a higher risk of treatment failure may provide a target population for treatment intensification by anti-CD20.

  4. Sole rearrangement but not amplification of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma and B cell lymphoma unclassifiable

    PubMed Central

    Landsburg, Daniel; Falkiewicz, Marissa; Petrich, Adam; Chu, Benjamin; Behdad, Amir; Li, Shaoying; Medeiros, L.; Cassaday, Ryan; Reddy, Nishitha; Bast, Martin; Vose, Julie; Kruczek, Kimberly; Smith, Scott; Patel, Priyank; Hernandez-Ilizaliturri, Francisco; Karmali, Reem; Rajguru, Saurabh; Yang, David; Maly, Joseph; Blum, Kristie; Zhao, Weiqiang; VanSlambrouck, Charles; Nabhan, Chadi

    2016-01-01

    Rearrangement of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable (BCLU), particularly in the setting of double hit lymphoma (DHL). Yet, little is known about outcomes of patients who demonstrate MYC rearrangement without evidence of BCL2 or BCL6 rearrangement (single hit) or amplification (>4 copies) of MYC. We identified 87 patients with single hit lymphoma (SHL), 22 patients with MYC-amplified lymphoma (MYC amp) as well as 127 DLBCL patients without MYC rearrangement or amplification (MYC normal) and 45 patients with double hit lymphoma (DHL), all treated with either R-CHOP or intensive induction therapy. For SHL and MYC amp patients, the 2 year progression free survival rate (2yPFS) was 49% and 48% and 2 year overall survival rate (2yOS) was 59% and 71%, respectively. SHL patients receiving intensive induction experienced higher 2yPFS (59% vs. 23%, P=0.006) but similar 2yOS as compared with SHL patients receiving R-CHOP. SHL DLBCL patients treated with R-CHOP, but not intensive induction, experienced significantly lower 2yPFS and 2yOS (p<0.001 for both) when compared with MYC normal patients. SHL patients appear to have a poor prognosis, which may be improved with receipt of intensive induction. PMID:27469075

  5. Stratifying diffuse large B-cell lymphoma patients treated with chemoimmunotherapy: GCB/non-GCB by immunohistochemistry is still a robust and feasible marker

    PubMed Central

    Batlle-López, Ana; de Villambrosía, Sonia González; Francisco, Mazorra; Malatxeberria, Sefora; Sáez, Anabel; Montalban, Carlos; Sánchez, Lydia; Garcia, Juan F.; González-Barca, Eva; López-Hernández, Andrés; Ruiz-Marcellan, MC; Mollejo, Manuela; Grande, Carlos; Richards, Kristy L.; Hsi, Eric D.; Tzankov, Alexandar; Visco, Carlo; Xu-Monette, Zijun Y.; Cao, Xin; Young, Ken H.; Piris, Miguel Ángel; Conde, Eulogio; Montes-Moreno, Santiago

    2016-01-01

    Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas that can be classified into three molecular subtypes by gene expression profiling (GEP): GCB, ABC and unclassified. Immunohistochemistry-based cell of origin (COO) classification, as a surrogate for GEP, using three available immunohistochemical algorithms was evaluated in TMA-arranged tissue samples from 297 patients with de novo DLBCL treated by chemoimmunotherapy (R-CHOP and R-CHOP-like regimens). Additionally, the prognostic impacts of MYC, BCL2, IRF4 and BCL6 abnormalities detected by FISH, the relationship between the immunohistochemical COO classification and the immunohistochemical expression of MYC, BCL2 and pSTAT3 proteins and clinical data were evaluated. In our series, non-GCB DLBCL patients had significantly worse progression-free survival (PFS) and overall survival (OS), as calculated using the Choi, Visco-Young and Hans algorithms, indicating that any of these algorithms would be appropriate for identifying patients who require alternative therapies to R-CHOP. Whilst MYC abnormalities had no impact on clinical outcome in the non-GCB subtype, those patients with isolated MYC rearrangements and a GCB-DLBCL phenotype had worse PFS and therefore might benefit from novel treatment approaches. PMID:26910115

  6. Comparison of Three Chemotherapy Regimens in Elderly Patients with Diffuse Large B Cell Lymphoma: Experience at a Single National Reference Center in Mexico

    PubMed Central

    Nolasco-Medina, Diana; Reynoso-Noveron, Nancy; Mohar-Betancourt, Alejandro; Aviles-Salas, Alejandro; García-Perez, Osvaldo

    2016-01-01

    Background. Although chemotherapy added to rituximab is a standard of care for diffuse large B cell lymphoma (DLBCL), treatment of patients ≥65 years of age remains controversial due to comorbidities. Methods. This is a retrospective, comparative, nonrandomized study of patients ≥65 years of age, who were diagnosed with DLBCL but not previously treated. Demographic characteristics and comorbidities were analyzed. Three rituximab-containing treatment regimens (standard RCHOP, anthracycline dose-reduced RChOP, and RCOP) were compared. Descriptive analyses were conducted. Survival was calculated with the Kaplan-Meier method, and differences were compared with the log-rank test. Results. In total, 141 patients with a median age of 73.9 years were studied. The three treatment groups had comparable demographic characteristics. The overall response was 77%, 72.5%, and 59% in groups treated with RCHOP, RChOP, and RCOP, respectively. After multivariate analysis, the factors influencing the overall survival were the presence of B symptoms, poor performance status (ECOG ≥ 3), and febrile neutropenia. Factors influencing disease-free survival were febrile neutropenia, high-intermediate and high-risk IPI scores, and treatment without anthracycline. Conclusion. A higher ORR (overall response rate) was achieved with standard RCHOP, which influenced DFS and OS, although it was not statistically significant compared with the other groups. Interventional phase 3 trials testing new molecules in patients aged 70 to 80 years and older are required to improve the prognosis within this growing population. PMID:27478844

  7. Impact of dose-dense immunochemotherapy on prognosis of germinal center and non germinal center origin of diffuse large B cell lymphoma.

    PubMed

    Rigacci, L; Puccini, B; Iovino, L; Martelli, M; Finolezzi, E; DI Lollo, S; Doria, M; Bosi, A

    2011-08-01

    Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Gene-expression profiling in DLCBL has brought insight into the biological heterogeneity of the disease. Two major subgroups have been identified: germinal center B (GCB) cell and non-germinal center (non-GCB). The aim of this study was to define retrospectively by immunohistochemistry the bcell origin of 69 patients treated with R-CHOP14 and to evaluate if dose-dense therapy could improve their clinical outcome. According to immunohistochemistry analysis 28 patients were derived from germinal center and 41 from non-germinal center. After a median period of observation of 46 months (range 3-101 months) the overall survival (OS) was 75% and progression-free survival (PFS) was 53% and no differences were observed according to cell origin. In conclusion, we can point out that intensification could enhance the efficacy of the R-CHOP regimen and improve overall survival in patients with non germinal lymphoma.

  8. Reduced-dose ICE chemotherapy ± rituximab is a safe and effective salvage therapy for fit elderly patients with diffuse large B-cell lymphoma.

    PubMed

    Sarid, Nadav; Joffe, Erel; Gibstein, Lili; Avivi, Irit; Polliack, Aaron; Perry, Chava; Herishanu, Yair

    2016-07-01

    The risk of developing non-Hodgkin lymphoma increases with age, yet elderly patients are under-represented in clinical trials. Here, we evaluate a combination regimen including ifosfamide, carboplatin and etoposide with or without rituximab (ICE ± R) in 32 fit elderly patients (median age 75.6 years) with relapsed or refractory diffuse large B-cell lymphoma. ICE ± R was generally administered in reduced doses and was well tolerated. The overall response rate (ORR) was 53.1% with a complete response (CR) rate of 40.6%. The median progression free survival (PFS) and overall survival (OS) were 3.9 and 17.0 months, respectively. Patients who responded to ICE ± R achieved median PFS of 47.2 months and OS of 78.9 months. Patients ineligible for autologous transplantation who responded to ICE ± R were treated with additional cycles, and achieved a median PFS of 18.9 months and OS of 21.7 months. Previous response to first-line therapy was the strongest predictor of response, PFS and OS to second-line treatment.

  9. PET/CT Scanner and Bone Marrow Biopsy in Detection of Bone Marrow Involvement in Diffuse Large B-Cell Lymphoma

    PubMed Central

    El Karak, Fadi; Bou-Orm, Ibrahim R.; Ghosn, Marwan; Kattan, Joseph; Farhat, Fadi; Ibrahim, Toni; Jreige, Mario; El Cheikh, Jean

    2017-01-01

    Evaluation of bone marrow involvement (BMI) is paramount in diffuse large B-cell lymphoma (DLBCL) for prognostic and therapeutic reasons. PET/CT scanner (PET) is now a routine examination for the staging of DLBCL with prognostic and therapeutic implications. This study evaluates the role of PET for detecting marrow involvement compared to bone marrow biopsy (BMB). This monocentric study included 54 patients diagnosed with DLBCL between 2009 and 2013 and who had FDG PET/CT in a pre-treatment setting. A correlation analysis of the detection of BMI by PET and BMB was performed. A prognostic evaluation of BMI by BMB and/or PET/CT and correlation with an overall 2-year survival were analyzed. PET was more sensitive for the detection of BMI than BMB (92.3% vs. 38.5%). It can be considered a discriminatory Pre-BMB test with a negative predictive value of 97.6%. In addition, BMI by PET had a prognostic value with strong correlation with progression-free survival (PFS) (HR = 3.81; p = 0.013) and overall survival (OS) (HR = 4.12; p = 0.03) while the BMB had not. PET shows superior performance to the BMB for the detection of marrow involvement in DLBCL. It may be considered as the first line examination of bone marrow instead of the biopsy. PMID:28099514

  10. Central nervous system involvement in diffuse large B-cell lymphoma: an analysis of risks and prevention strategies in the post-rituximab era.

    PubMed

    Fletcher, Christopher D; Kahl, Brad S

    2014-10-01

    Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) occurs infrequently (approximately 5%), but is almost universally fatal. Controversy exists regarding which factors most reliably identify high risk patients in the post-rituximab era. Clarification is also needed regarding the value of prophylaxis strategies when contemporary rituximab-based chemotherapy regimens (chemoimmunotherapy) are used. A systematic review with focus on the era of chemoimmunotherapy has been performed. Involvement of > 1 extranodal site plus an elevated lactate dehydrogenase level identifies individuals at highest risk (> 20%) for CNS recurrence who merit additional evaluation. Only certain solitary extranodal sites (testis, kidney and breast, but not bones, orbit or epidural space) appear to confer higher risk in patients receiving chemoimmunotherapy. Data from studies employing modern regimens suggest that intrathecal prophylaxis is ineffective even for high risk populations. Systemic prophylaxis (e.g. high dose methotrexate) may be useful, but does not have strong support in the literature. A significant portion of patients with high risk features (˜25%) may already have subclinical CNS disease, which requires alternative detection and treatment strategies. Flow cytometry is a promising approach with increased sensitivity. Widespread use of this approach could redefine what risk and prophylaxis mean. An algorithm for incorporating risk factors, evaluation and treatment is presented.

  11. Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma.

    PubMed

    Feldman, Tatyana; Mato, Anthony R; Chow, Kar F; Protomastro, Ewelina A; Yannotti, Kara M L; Bhattacharyya, Pritish; Yang, Xiao; Donato, Michele L; Rowley, Scott D; Carini, Carolanne; Valentinetti, Marisa; Smith, Judith; Gadaleta, Gabriella; Bejot, Coleen; Stives, Susan; Timberg, Mary; Kdiry, Sabrina; Pecora, Andrew L; Beaven, Anne W; Goy, Andre

    2014-07-01

    Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis. Outcomes are particularly poor following immunochemotherapy failure or relapse within 12 months of induction. We conducted a Phase I/II trial of lenalidomide plus RICE (rituximab, ifosfamide, carboplatin, and etoposide) (RICER) as a salvage regimen for first-relapse or primary refractory DLBCL. Dose-escalated lenalidomide was combined with RICE every 14 d. After three cycles of RICER, patients with chemosensitive disease underwent stem cell collection and consolidation with BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan] followed by autologous stem cell transplantation (autoSCT). Patients who recovered from autoSCT toxicities within 90 d initiated maintenance treatment with lenalidomide 25 mg daily for 21 d every 28 d for 12 months. No dose-limiting or unexpected toxicities occurred with lenalidomide 25 mg plus RICE. Grade 3/4 haematological toxicities resolved appropriately, and planned dose density and dose intensity of RICER were preserved. No lenalidomide or RICE dose reductions were required in any of the three cycles. After two cycles of RICER, nine of 15 patients (60%) achieved a complete response, and two achieved a partial response (13%). Combining lenalidomide with RICE is feasible, and results in promising response rates (particularly complete response rates) in high-risk DLBCL patients.

  12. Diffuse large B-cell lymphoma with concurrent high MYC and BCL2 expression shows evidence of active B-cell receptor signaling by quantitative immunofluorescence

    PubMed Central

    Kovach, Alexandra E.; Le, Long P.; Feng, Derek; Baxter, Richard H. G.; Sohani, Aliyah R.

    2017-01-01

    B-cell receptor (BCR)-mediated signaling plays an important role in the pathogenesis of a subset of diffuse large B-cell lymphoma (DLBCL), and novel agents targeting this pathway are now in clinical use. We have previously identified a signature of active BCR signaling on formalin-fixed paraffin-embedded specimens using quantitative immunofluorescence, allowing for identification of patients who might benefit from anti-BCR therapies. We sought to characterize the clinicopathologic significance of active BCR signaling in DLBCL by correlating measures of signaling intensity with clinical features and various tumor cell characteristics. High MYC and concurrent high MYC and BCL2 double-expression was positively correlated with individual markers of active BCR signaling and cases with MYC/BCL2 double-expression showed overall greater BCR activation compared to cases lacking double-expression. Our findings suggest that the BCR signaling pathway may be more active in MYC/BCL2 double-expressor DLBCL and may represent a rational therapeutic target in this aggressive DLBCL subgroup. PMID:28212447

  13. Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy.

    PubMed

    Gutiérrez-García, Gonzalo; Cardesa-Salzmann, Teresa; Climent, Fina; González-Barca, Eva; Mercadal, Santiago; Mate, José L; Sancho, Juan M; Arenillas, Leonor; Serrano, Sergi; Escoda, Lourdes; Martínez, Salomé; Valera, Alexandra; Martínez, Antonio; Jares, Pedro; Pinyol, Magdalena; García-Herrera, Adriana; Martínez-Trillos, Alejandra; Giné, Eva; Villamor, Neus; Campo, Elías; Colomo, Luis; López-Guillermo, Armando

    2011-05-05

    Diffuse large B-cell lymphomas (DLBCLs) can be divided into germinal-center B cell-like (GCB) and activated-B cell-like (ABC) subtypes by gene-expression profiling (GEP), with the latter showing a poorer outcome. Although this classification can be mimicked by different immunostaining algorithms, their reliability is the object of controversy. We constructed tissue microarrays with samples of 157 DLBCL patients homogeneously treated with immunochemotherapy to apply the following algorithms: Colomo (MUM1/IRF4, CD10, and BCL6 antigens), Hans (CD10, BCL6, and MUM1/IRF4), Muris (CD10 and MUM1/IRF4 plus BCL2), Choi (GCET1, MUM1/IRF4, CD10, FOXP1, and BCL6), and Tally (CD10, GCET1, MUM1/IRF4, FOXP1, and LMO2). GEP information was available in 62 cases. The proportion of misclassified cases by immunohistochemistry compared with GEP was higher when defining the GCB subset: 41%, 48%, 30%, 60%, and 40% for Colomo, Hans, Muris, Choi, and Tally, respectively. Whereas the GEP groups showed significantly different 5-year progression-free survival (76% vs 31% for GCB and activated DLBCL) and overall survival (80% vs 45%), none of the immunostaining algorithms was able to retain the prognostic impact of the groups (GCB vs non-GCB). In conclusion, stratification based on immunostaining algorithms should be used with caution in guiding therapy, even in clinical trials.

  14. High incidence of Kaposi sarcoma-associated herpesvirus infection in HIV-related solid immunoblastic/plasmablastic diffuse large B-cell lymphoma.

    PubMed

    Deloose, S T P; Smit, L A; Pals, F T; Kersten, M-J; van Noesel, C J M; Pals, S T

    2005-05-01

    Kaposi sarcoma-associated herpesvirus (KSHV) is known to be associated with two distinct lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD)/MCD-associated plasmablastic lymphoma. We here report a high incidence of KSHV infection in solid HIV-associated immunoblastic/plasmablastic non-Hodgkin's lymphomas (NHLs), in patients lacking effusions and without evidence of (prior) MCD. Within a cohort of 99 HIV-related NHLs, 10 cases were found to be KSHV positive on the basis of immunostaining for KSHV LNA-1 as well as KSHV-specific polymerase chain reaction. All but one of the tumors coexpressed Epstein-Barr virus. Interestingly, all KSHV-positive cases belonged to a distinctive subgroup of 26 diffuse large B-cell lymphomas characterized by the expression of CD138 (syndecan-1) and plasmablastic/immunoblastic morphology. These KSHV-positive lymphomas were preceded by Kaposi sarcoma in 60% of the patients and involved the gastrointestinal tract in 80%. Our results indicate that KSHV infection is not restricted to PEL and MCD; it is also common (38%) in HIV-related solid immunoblastic/plasmablastic lymphomas.

  15. The impact of FcγRIIa and FcγRIIIa gene polymorphisms on responses to RCHOP chemotherapy in diffuse large B-cell lymphoma patients

    PubMed Central

    ROŽMAN, SAMO; NOVAKOVIĆ, SRDJAN; GRABNAR, IZTOK; CERKOVNIK, PETRA; NOVAKOVIĆ, BARBARA JEZERŠEK

    2016-01-01

    Rituximab is a monoclonal antibody routinely used in the treatment of B-cell non-Hodgkin lymphomas. It mediates antibody-dependent cellular cytotoxicity of B lymphocytes by bridging them with Fcγ receptors (FcγR) on effector cells. Several polymorphisms in the FcγR genes have been identified to influence rituximab binding to FcγR, thus altering its antitumor effect in indolent lymphomas. In the present study, the impact of FcγRIIa and FcγRIIIa polymorphisms on the survival and response to immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone was evaluated in diffuse large B-cell lymphoma (DLBCL) patients. A total of 29 Slovenian DLBCL patients were studied. Genotyping was conducted for FcγRIIa-27, FcγRIIa-131, FcγRIIIa-48 and FcγRIIIa-158 polymorphisms. The median follow-up time was 29.7 months (range, 9.7–45.4 months). No significant impact of the genotypes was observed on the treatment response, progression-free or overall survival of DLBCL patients. There was a non-significant trend of an improved response to chemotherapy without additional irradiation in patients homozygous for Val at FCγIIIa-158 compared to Phe carriers. The findings of the present study indicate that FcγR polymorphisms have no influence on the survival of DLBCL patients. PMID:27123112

  16. Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth.

    PubMed

    Pizzi, Marco; Piazza, Francesco; Agostinelli, Claudio; Fuligni, Fabio; Benvenuti, Pietro; Mandato, Elisa; Casellato, Alessandro; Rugge, Massimo; Semenzato, Gianpietro; Pileri, Stefano A

    2015-03-30

    Serine-threonine kinase CK2 is highly expressed and pivotal for survival and proliferation in multiple myeloma, chronic lymphocytic leukemia and mantle cell lymphoma. Here, we investigated the expression of α catalytic and β regulatory CK2 subunits by immunohistochemistry in 57 follicular (FL), 18 Burkitt (BL), 52 diffuse large B-cell (DLBCL) non-Hodgkin lymphomas (NHL) and in normal reactive follicles. In silico evaluation of available Gene Expression Profile (GEP) data sets from patients and Western blot (WB) analysis in NHL cell-lines were also performed. Moreover, the novel, clinical-grade, ATP-competitive CK2-inhibitor CX-4945 (Silmitasertib) was assayed on lymphoma cells. CK2 was detected in 98.4% of cases with a trend towards a stronger CK2α immunostain in BL compared to FL and DLBCL. No significant differences were observed between Germinal Center B (GCB) and non-GCB DLBCL types. GEP data and WB confirmed elevated CK2 mRNA and protein levels as well as active phosphorylation of specific targets in NHL cells. CX-4945 caused a dose-dependent growth-arresting effect on GCB, non-GCB DLBCL and BL cell-lines and it efficiently shut off phosphorylation of NF-κB RelA and CDC37 on CK2 target sites. Thus, CK2 is highly expressed and could represent a suitable therapeutic target in BL, FL and DLBCL NHL.

  17. Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth

    PubMed Central

    Agostinelli, Claudio; Fuligni, Fabio; Benvenuti, Pietro; Mandato, Elisa; Casellato, Alessandro; Rugge, Massimo; Semenzato, Gianpietro; Pileri, Stefano A.

    2015-01-01

    Serine-threonine kinase CK2 is highly expressed and pivotal for survival and proliferation in multiple myeloma, chronic lymphocytic leukemia and mantle cell lymphoma. Here, we investigated the expression of α catalytic and β regulatory CK2 subunits by immunohistochemistry in 57 follicular (FL), 18 Burkitt (BL), 52 diffuse large B-cell (DLBCL) non-Hodgkin lymphomas (NHL) and in normal reactive follicles. In silico evaluation of available Gene Expression Profile (GEP) data sets from patients and Western blot (WB) analysis in NHL cell-lines were also performed. Moreover, the novel, clinical-grade, ATP-competitive CK2-inhibitor CX-4945 (Silmitasertib) was assayed on lymphoma cells. CK2 was detected in 98.4% of cases with a trend towards a stronger CK2α immunostain in BL compared to FL and DLBCL. No significant differences were observed between Germinal Center B (GCB) and non-GCB DLBCL types. GEP data and WB confirmed elevated CK2 mRNA and protein levels as well as active phosphorylation of specific targets in NHL cells. CX-4945 caused a dose-dependent growth-arresting effect on GCB, non-GCB DLBCL and BL cell-lines and it efficiently shut off phosphorylation of NF-κB RelA and CDC37 on CK2 target sites. Thus, CK2 is highly expressed and could represent a suitable therapeutic target in BL, FL and DLBCL NHL. PMID:25788269

  18. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma.

    PubMed

    Milhollen, Michael A; Traore, Tary; Adams-Duffy, Jennifer; Thomas, Michael P; Berger, Allison J; Dang, Lenny; Dick, Lawrence R; Garnsey, James J; Koenig, Erik; Langston, Steven P; Manfredi, Mark; Narayanan, Usha; Rolfe, Mark; Staudt, Louis M; Soucy, Teresa A; Yu, Jie; Zhang, Julie; Bolen, Joseph B; Smith, Peter G

    2010-09-02

    MLN4924 is a potent and selective small molecule NEDD8-activating enzyme (NAE) inhibitor. In most cancer cells tested, inhibition of NAE leads to induction of DNA rereplication, resulting in DNA damage and cell death. However, in preclinical models of activated B cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), we show that MLN4924 induces an alternative mechanism of action. Treatment of ABC DLBCL cells with MLN4924 resulted in rapid accumulation of pIkappaBalpha, decrease in nuclear p65 content, reduction of nuclear factor-kappaB (NF-kappaB) transcriptional activity, and G(1) arrest, ultimately resulting in apoptosis induction, events consistent with potent NF-kappaB pathway inhibition. Treatment of germinal-center B cell-like (GCB) DLBCL cells resulted in an increase in cellular Cdt-1 and accumulation of cells in S-phase, consistent with cells undergoing DNA rereplication. In vivo administration of MLN4924 to mice bearing human xenograft tumors of ABC- and GCB-DLBCL blocked NAE pathway biomarkers and resulted in complete tumor growth inhibition. In primary human tumor models of ABC-DLBCL, MLN4924 treatment resulted in NF-kappaB pathway inhibition accompanied by tumor regressions. This work describes a novel mechanism of targeted NF-kappaB pathway modulation in DLBCL and provides strong rationale for clinical development of MLN4924 against NF-kappaB-dependent lymphomas.

  19. Renal Infiltration by Diffuse Large B-Cell Lymphoma as a Rare Cause of Fanconi’s Syndrome: A Case Report

    PubMed Central

    Mahmud, Syed Nayer; Qureshi, Asim

    2016-01-01

    We report the case of a 16-year-old female patient with a known history of coeliac disease, who presented with the complaints of diarrhea, vomiting and generalized body weakness. On examination, she was found to have dehydration, decreased power in all her limbs, cervical lymphadenopathy and hepatosplenomegaly. Investigations showed severe hypokalemia, hyponatremia, hypomagnesemia, hypoglycemia and mildly enlarged kidneys on ultrasonography. Biopsy of the duodenum confirmed the flare up of coeliac disease, while cervical lymph node biopsy was positive for atypical lymphoid infiltrate and a morphology suggestive of non-Hodgkin’s lymphoma. The immune profile performed on this sample confirmed the presence of activated/non-germinal center type of diffuse large B cell lymphoma (DLBCL), which was morphologically aggressive in type. The bone marrow biopsy was hypocellular and was negative for any infiltration. The patient was suspected to have developed infiltration of one or both kidneys leading to a rare presentation of Fanconi’s syndrome. She was given first dose of rituximab on the 14th day of her admission. Unfortunately, she developed cardiopulmonary arrest and expired on the next day. We recommend screening for a possible renal involvement in patients with DLBCL and in patients with unusually deranged serum electrolytes as seen in Fanconi’s syndrome. Renal biopsy is considered the gold standard modality for diagnosis and if possible, an earlier sample in a patient with newly developed acute kidney injury can save future complications. PMID:28070473

  20. Long-term survival of diffuse large B cell lymphoma of the trigeminal region extending to the Meckel's cave treated by CHASER therapy: case report.

    PubMed

    Tanaka, Toshihide; Kato, Naoki; Itoh, Kuniaki; Hasegawa, Yuzuru

    2014-01-01

    A 52-year-old man with a history of malignant lymphoma of the cecum presented with lancinating facial pain in the left. Magnetic resonance imaging (MRI) revealed a tumor in the Meckel's cave extending along the trigeminal nerve. The tumor was partially removed via left retrosigmoid lateral suboccipital craniotomy. Histological examination showed findings consistent with diffuse large B cell lymphoma, which was later confirmed to be metastatic lesion from the cecal lesion. Postoperative chemotherapy with cyclophosphamide, high dose, cytarabine, steroid (dexamethasone), etoposide, and rituximab (CHASER) followed by whole brain irradiation (30 Gy) resulted in complete remission. Although facial pain persisted, the patient's general condition remained favorable and he did not experience recurrence over the 51-month follow-up period. Histological confirmation and awareness of malignant lymphoma are very important to determine the therapeutic strategy and to avoid misdiagnosis or delayed diagnosis. Long-term survival of patients with metastatic malignant lymphoma in the Meckel's cave extending along the trigeminal nerve was very rare. In addition, metastatic malignant lymphoma in the extra-axial and peripheral nervous tissue might be different from primary central nervous system lymphoma in the white matter, since the efficacy of chemotherapeutic agents against malignant lymphomas in the extra-axial regions is not attenuated by the blood brain barrier.

  1. Population-specific prognostic models are needed to stratify outcomes for African-Americans with diffuse large B-cell lymphoma.

    PubMed

    Chen, Qiushi; Ayer, Turgay; Nastoupil, Loretta J; Koff, Jean L; Staton, Ashley D; Chhatwal, Jagpreet; Flowers, Christopher R

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) demonstrates significant racial differences in age of onset, stage, and survival. To examine whether population-specific models improve prediction of outcomes for African-American (AA) patients with DLBCL, we utilized Surveillance, Epidemiology, and End Results data and compared stratification by the international prognostic index (IPI) in general and AA populations. We also constructed and compared prognostic models for general and AA populations using multivariable logistic regression (LR) and artificial neural network approaches. While the IPI adequately stratified outcomes for the general population, it failed to separate AA DLBCL patients into distinct risk groups. Our AA LR model identified age ≥ 55 (odds ratio 0.45, [95% CI: 0.36, 0.56], male sex (0.75, [0.60, 0.93]), and stage III/IV disease (0.43, [0.34, 0.54]) as adverse predictors of 5-year survival for AA patients. In addition, general-population prognostic models were poorly calibrated for AAs with DLBCL, indicating a need for validated AA-specific prognostic models.

  2. EBV-positive diffuse large B-cell lymphoma of the elderly: 2016 update on diagnosis, risk-stratification, and management.

    PubMed

    Castillo, Jorge J; Beltran, Brady E; Miranda, Roberto N; Young, Ken H; Chavez, Julio C; Sotomayor, Eduardo M

    2016-05-01

    Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is a provisional entity included in the 2008 WHO classification of lymphoid neoplasms. It is a disease typically seen in the elderly and thought to be associated with chronic EBV infection and severe immunosuppression with a component of immunosenescence. Recent research, however, has suggested that EBV-positive DLBCL can be seen in younger, immunocompetent patients. The diagnosis of EBV-positive DLBCL of the elderly is made through a careful pathological evaluation. The differential diagnosis includes infectious mononucleosis (specifically in younger patients), lymphomatoid granulomatosis, Hodgkin lymphoma, and gray zone lymphoma, among others. Detection of EBV-encoded RNA (EBER) is considered standard for diagnosis; however, a clear cutoff for positivity has not been defined. The International Prognostic Index (IPI), and the Oyama score can be used for risk-stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 is emerging as a potential adverse, and targetable, prognostic factor. Patients with EBV-positive DLBCL should be staged and managed following similar guidelines than patients with EBV-negative DLBCL. It has been suggested, however, that EBV-positive patients have a worse prognosis than EBV-negative counterparts in the era of chemoimmunotherapy. There is an opportunity to study and develop targeted therapy in the management of patients with EBV-positive DLBCL.

  3. Inhibition of MALT1 protease activity is selectively toxic for activated B cell-like diffuse large B cell lymphoma cells.

    PubMed

    Ferch, Uta; Kloo, Bernhard; Gewies, Andreas; Pfänder, Vera; Düwel, Michael; Peschel, Christian; Krappmann, Daniel; Ruland, Jürgen

    2009-10-26

    Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoma in humans. The aggressive activated B cell-like (ABC) subtype of DLBCL is characterized by constitutive NF-kappaB activity and requires signals from CARD11, BCL10, and the paracaspase MALT1 for survival. CARD11, BCL10, and MALT1 are scaffold proteins that normally associate upon antigen receptor ligation. Signal-induced CARD11-BCL10-MALT1 (CBM) complexes couple upstream events to IkappaB kinase (IKK)/NF-kappaB activation. MALT1 also possesses a recently recognized proteolytic activity that cleaves and inactivates the negative NF-kappaB regulator A20 and BCL10 upon antigen receptor ligation. Yet, the relevance of MALT1 proteolytic activity for malignant cell growth is unknown. Here, we demonstrate preassembled CBM complexes and constitutive proteolysis of the two known MALT1 substrates in ABC-DLBCL, but not in germinal center B cell-like (GCB) DLBCL. ABC-DLBCL cell treatment with a MALT1 protease inhibitor blocks A20 and BCL10 cleavage, reduces NF-kappaB activity, and decreases the expression of NF-kappaB targets genes. Finally, MALT1 paracaspase inhibition results in death and growth retardation selectively in ABC-DLBCL cells. Thus, our results indicate a growth-promoting role for MALT1 paracaspase activity in ABC-DLBCL and suggest that a pharmacological MALT1 protease inhibition could be a promising approach for lymphoma treatment.

  4. Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-κB activation in diffuse large B-cell lymphoma.

    PubMed

    Qu, Changju; Liu, Yadong; Kunkalla, Kranthi; Singh, Rajesh R; Blonska, Marzenna; Lin, Xin; Agarwal, Nitin Kumar; Vega, Francisco

    2013-06-06

    Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Aberrant activation of Hedgehog (Hh) and nuclear factor (NF)-κB pathways is ubiquitously observed and known to mediate tumor growth, survival, and chemoresistance in DLBCL. Here, we find that activation of Hh signaling is positively correlated with NF-κB pathway in DLBCL tumors, and that smoothened (SMO), the signal transducer subunit of Hh pathway, contributes to NF-κB activation through recruiting G protein subunits Gαi and Gα12 to activate PKCβ/CARMA1/TRAF6/NEMO signaling axis followed by assembling of the CARMA1/BCL10/MALT1/TRAF6 complex to SMO. Moreover, functional inhibition of SMO enhances the cytotoxic effects of NF-κB inhibitor. Altogether, our study reveals a noncanonical Hh signaling pathway in which SMO activates trimeric G proteins and CARMA1-associated signaling complex, leading to NF-κB activation. This signaling cascade contributes to the survival of DLBCL and may serve as a potential target for combination therapies in DLBCL.

  5. Methylation changes of SIRT1, KLF4, DAPK1 and SPG20 in B-lymphocytes derived from follicular and diffuse large B-cell lymphoma.

    PubMed

    Frazzi, Raffaele; Zanetti, Eleonora; Pistoni, Mariaelena; Tamagnini, Ione; Valli, Riccardo; Braglia, Luca; Merli, Francesco

    2017-03-09

    Diffuse large-B cell lymphomas (DLBCL) and follicular lymphomas (FL) are the most represented subtypes among mature B-cell neoplasms and originate from malignant B lymphocytes. Methylation represents one of the major epigenetic mechanisms of gene regulation. Silent information regulator 1 (SIRT1) is a class III lysine-deacetylase playing several functions and considered to be a context-dependent tumor promoter. We present the quantitative methylation, gene expression and tissue distribution of SIRT1 and some key mediators related to lymphoma pathogenesis in B lymphocytes purified from biopsies of follicular hyperplasias, FL and DLBCL. SIRT1 mRNA levels are higher in FL than follicular hyperplasias and DLBCL. B cell lymphoma 6 (BCL6) positively correlates with SIRT1. SIRT1 promoter shows a methylation decrease in the order: follicular hyperplasia - FL - DLBCL. Kruppel-like factor 4 (KLF4), Death-associated protein kinase 1 (DAPK1) and Spastic Paraplegia 20 (SPG20) methylation increase significantly in FL and DLBCL compared to follicular hyperplasias. Gene expression of DAPK1 and SPG20 inversely correlates with their degree of methylation. Our findings evidence a positive correlation between SIRT1 and BCL6 expression increase in FL. SIRT1 methylation decreases in FL and DLBCL accordingly and this parallels the increase of KLF4, DAPK1 and SPG20 methylation.

  6. White matter integrity assessed by diffusion tensor tractography in a patient with a large tumor mass but minimal clinical and neuropsychological deficits

    PubMed Central

    Bozzali, Marco; MacPherson, Sarah E.; Cercignani, Mara; Crum, William R.; Shallice, Tim; Rees, Jeremy H.

    2012-01-01

    Summary Diffusion tensor imaging (DTI) tractography and image registration were used to investigate a patient with a massive left-sided brain tumor, whose size was largely disproportionate to his subtle neurological deficits. MRI was obtained from the patient and his healthy identical twin, who acted as anatomical reference for DTI and as a control for quantitative measures. To compensate for the patient’s altered anatomy, seed and way points for probabilistic tractography were drawn on the color-coded direction maps of the healthy twin. Registration, based on the combination of b0-images, T2-weighted and T1-weighted images, was used to identify the corresponding regions in the patient. The corticospinal tract (CST), the superior longitudinal fasciculus (SLF), and the cingulum bundle (CB) showed displaced anatomy. A significant difference was found between fractional anisotropy distribution along the left SLF and CB, but not along the CST. These findings fit well with the patient’s substantial preservation of his motor abilities, while abnormalities of the SLF and CB could explain the subtle but detectable cognitive deficits. PMID:23597438

  7. Hepatitis B virus-associated diffuse large B-cell lymphoma: unique clinical features, poor outcome, and hepatitis B surface antigen-driven origin.

    PubMed

    Deng, Lijuan; Song, Yuqin; Young, Ken H; Hu, Shimin; Ding, Ning; Song, Weiwei; Li, Xianghong; Shi, Yunfei; Huang, Huiying; Liu, Weiping; Zheng, Wen; Wang, Xiaopei; Xie, Yan; Lin, Ningjing; Tu, Meifeng; Ping, Lingyan; Ying, Zhitao; Zhang, Chen; Sun, Yingli; Zhu, Jun

    2015-09-22

    While the epidemiologic association between hepatitis B virus (HBV) infection and diffuse large B-cell lymphoma (DLBCL) is established, little is known more than this epidemiologic evidence. We studied a cohort of 587 patients with DLBCL for HBV infection status, clinicopathologic features, and the immunoglobulin variable region in HBV surface antigen (HBsAg)-positive patients. Eighty-one (81/587, 13.8%) patients were HBsAg-positive. Compared with HBsAg-negative DLBCL, HBsAg-positive DLBCL displayed a younger median onset age (45 vs. 55 years), more frequent involvement of spleen or retroperitoneal lymph node (40.7% vs. 16.0% and 61.7% vs. 31.0% respectively, both p < 0.001), more advanced disease (stage III/IV: 76.5% vs 59.5%, p = 0.003), and significantly worse outcome (2-year overall survival: 47% versus 70%, p < 0.001). In HBsAg-positive DLBCL patients, almost all (45/47, 96%) amino acid sequences of heavy and light chain complementarity determining region 3 exhibited a high homology to antibodies specific for HBsAg, and the majority (45/50, 90%) of IgHV and IgLV genes were mutated. We conclude that 13.8% of DLBCL cases are HBV-associated in HBV-endemic China and show unique clinical features and poor outcomes. Furthermore, our study strongly suggests that HBV-associated DLBCL might arise from HBV antigen-selected B cells.

  8. Using the pathology report in initial treatment decisions for diffuse large B-cell lymphoma: time for a precision medicine approach.

    PubMed

    Friedberg, Jonathan W

    2015-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non Hodgkin lymphoma in the Western world, and is potentially curable with standard R-CHOP chemoimmunotherapy. Historically, clinical risk assessments provided prognostic information, but did not define treatment approach. We are now in an era where the heterogeneity of DLBCL is defined genetically and molecularly, and rational subset-specific therapeutic targets are guiding clinical trials. Primary mediastinal DLBCL is a unique clinicopathologic entity, and alternatives to R-CHOP may confer superior outcome. Rearrangement of the myc oncogene occurs in ~10% of patients with DLBCL, and confers a very poor prognosis with standard R-CHOP, particularly when there is concomitant rearrangement of bcl-2, a condition referred to as "double-hit" DLBCL. A larger subset of DLBCL demonstrates overexpression of both myc and bcl-2 by immunohistochemistry. Cell of origin, determined by gene expression analysis, immunohistochemistry algorithms, or a novel Lymph2Cx platform, provides prognostic information, and guides therapeutic decisions in both relapsed and de novo disease. This article will define specific subsets of DLBCL and provide subtype-specific treatment options, including novel approaches under investigation. Understanding these key features of the pathology report, and limitations of these assays defining subsets of DLBCL, allows for an evolving precision medicine approach to this disease.

  9. Circulating CXCR5+CD4+ T cells assist in the survival and growth of primary diffuse large B cell lymphoma cells through interleukin 10 pathway.

    PubMed

    Cha, Zhanshan; Qian, Guangfang; Zang, Yan; Gu, Haihui; Huang, Yanyan; Zhu, Lishuang; Li, Jinqi; Liu, Yang; Tu, Xiaohua; Song, Haihan; Qian, Baohua

    2017-01-01

    Diffuse large B cell lymphoma (DLBCL) is a common and aggressive cancer caused by the malignant transformation of B cells. Although it has been established that the follicular helper T (Tfh) cells play a central role in B cell development, little information is available on their involvement in DLBCL pathogenesis. We studied the role of the peripheral Tfh equivalent, the CXCR5(+) CD4(+) T cells, in DLBCL. Data showed that compared to CXCR5(-) CD4(+) T cells, CXCR5(+) CD4(+) T cells were significantly more effective at promoting the proliferation as well as inhibiting the apoptosis of primary autologous DLBCL tumor cells. Surprisingly, we found that at equal cell numbers, CXCR5(+) CD4(+) T cells in DLBCL patients secreted significantly less interleukin (IL)-21 than CXCR5(-) CD4(+) T cells, while the level of IL-10 secretion was significant elevated in the CXCR5(+) compartment compared to the CXCR5(-) compartment. Neutralization of IL-10 in the primary DLBCL-CXCR5(+) CD4(+) T cell coculture compromised the CXCR5(+) CD4(+) T cell-mediated pro-tumor effects, in a manner that was dependent on the concentration of anti-IL-10 antibodies. The CXCR5(+) compartment also contained significantly lower frequencies of cytotoxic CD4(+) T cells than the CXCR5(-) compartment. In conclusion, our investigations discovered a previously unknown pro-tumor role of CXCR5-expressing circulating CD4(+) T cells, which assisted the survival and proliferation of primary DLBCL cells through IL-10.

  10. Peat porewaters have contrasting geochemical fingerprints for groundwater recharge and discharge due to matrix diffusion in a large, northern bog-fen complex

    NASA Astrophysics Data System (ADS)

    Levy, Zeno F.; Siegel, Donald I.; Glaser, Paul H.; Samson, Scott D.; Dasgupta, Soumitri S.

    2016-10-01

    Although northern peatlands represent a globally significant reservoir for carbon, considerable uncertainty exists concerning solute transport systems within large (>1000 km2) peat deposits. We therefore delineated geochemical gradients linked to groundwater recharge and discharge along a 6 km transect within the 1200 km2 Red Lake Peatland of northwestern Minnesota. We used ratios of Ca/Mg and 87Sr/86Sr to distinguish discharge of calcareous groundwater (∼1.4 and 0.7155, respectively) to the peatland from the mineral substratum along a topographic gradient from a bog crest downslope to an internal fen water track and bog islands. In contrast, the stable isotopes of the porewaters (δ18O from -12.8 ‰ to -7.8 ‰) show that the active pore-spaces in these peat profiles have been flushed by recharge from the near-surface peat. We hypothesize that back-diffusion of groundwater-derived solutes from the peat matrix to active pore-spaces has allowed the geochemical signal from paleo-hydrogeologic discharge to persist into the current regime of dilute recharge. This effect has not been observed previously on the landform-scale and has important implications for carbon cycling in peatlands.

  11. Safety and efficacy of rituximab plus bendamustine in relapsed or refractory diffuse large B-cell lymphoma patients: an Italian retrospective multicenter study.

    PubMed

    Arcari, Annalisa; Chiappella, Annalisa; Spina, Michele; Zanlari, Luca; Bernuzzi, Patrizia; Valenti, Vanessa; Tani, Monica; Marasca, Roberto; Cabras, Maria Giuseppina; Zambello, Renato; Santagostino, Alberto; Ilariucci, Fiorella; Carli, Giuseppe; Musto, Pellegrino; Savini, Paolo; Marino, Dario; Ghio, Francesco; Gentile, Massimo; Cox, Maria Christina; Vallisa, Daniele

    2016-08-01

    Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not suitable for high dose chemotherapy with autologous stem cell transplantation (ASCT) has a dismal prognosis and no standard therapy. We designed an Italian multicenter retrospective study aimed at evaluating the safety and efficacy of rituximab plus bendamustine (R-B) as salvage treatment in patients not eligible for ASCT because of age and/or comorbidity or in patients with post-ASCT recurrence. Fifty-five patients with a median age of 76 years were included. The overall response rate was 50%, including 28% complete remission and 22% partial remission. The median overall survival (OS) was 10.8 months. The median progression free survival (PFS) was 8.8 months. Eleven patients are still alive and in complete remission at last follow-up (12-71 months). Toxicity was moderate, mainly grades 1 and 2. R-B showed promising efficacy results with an acceptable toxicity profile and should be further investigated, possibly in combination with novel drugs.

  12. Molecular analysis of a chromosomal translocation, t(9;14)(p13;q32), in a diffuse large-cell lymphoma cell line expressing the Ki-1 antigen.

    PubMed Central

    Ohno, H; Furukawa, T; Fukuhara, S; Zong, S Q; Kamesaki, H; Shows, T B; Le Beau, M M; McKeithan, T W; Kawakami, T; Honjo, T

    1990-01-01

    We have studied a translocation, t(9;14)(p13;q32), in a diffuse large-cell lymphoma cell line, KIS-1, that expresses the Ki-1 (CD30) antigen. Molecular cloning of the immunoglobulin heavy-chain locus (IGH) of this cell line revealed an unknown segment linked 5' to IGH. The breakpoint on chromosome 14 was 265 base pairs downstream from the 3' border of the JH6 joining gene segment. Class switch recombination deleted most of the constant genes of IGH (CH) and juxtaposed the C alpha 2 gene downstream of the translocation junction. Analysis of somatic cell hybrids and in situ chromosomal hybridization demonstrated that the translocated segment was normally located at band p13 of chromosome 9. The chromosome 9 sequences were transcriptionally active, giving rise to transcripts of approximately 11 kilobases. The KIS-1 cells seemed to have a small quantity of chimeric transcripts containing both chromosome 9 and C alpha 2 sequences. Images PMID:2153959

  13. R-CHOP-14 in patients with diffuse large B-cell lymphoma younger than 70 years: a multicentre, prospective study.

    PubMed

    Rueda, Antonio; Sabin, Pilar; Rifá, Juli; Llanos, Marta; Gómez-Codina, José; Lobo, Francisco; García, Ramón; Herrero, Joaquin; Provencio, Mariano; Jara, Carlos

    2008-03-01

    Several studies have shown that adding rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or reducing the interval between chemotherapy cycles from 3 weeks to 2 weeks improves survival in patients with diffuse large B-cell lymphoma (DLBCL). These studies prompted our group (GOTEL) to evaluate prospectively in a pilot study the feasibility and efficacy of R-CHOP-14 in patients with DLBCL. Patients (<70 years) with stage II bulky or stage III or IV DLBCL and no significant comorbidities were included in the study. Rituximab was administered on day 1 before chemotherapy. R-CHOP was given every 14 days. All patients received filgrastim (5 microg/kg) from days 4 to 10. From May 2002 to August 2004, 80 patients were recruited. Median age was 53 years and 58 patients were <60 years. According to the age-adjusted international prognostic index (aaIPI), 13 patients (16%) had low-risk disease, 31 (39%) low-to-intermediate risk, 27 (34%) high-to-intermediate risk and 9 (11%) high-risk disease. Grade 3-4 neutropenia was observed in 15 patients (17.5%) and grade 3-4 infections in 13 patients (16%). After therapy, 58 patients (73%) achieved CR-CRu (95% CI: 55-90%). With a median follow-up of 26 months, progression-free survival (PFS) and overall survival (OS) at 30 months were 72% and 86%, respectively. Administration of R-CHOP-14 is feasible and effective in patients <70 years.

  14. MCL-1-independent mechanisms of synergy between dual PI3K/mTOR and BCL-2 inhibition in diffuse large B cell lymphoma

    PubMed Central

    Lee, J. Scott; Tang, Sarah S.; Ortiz, Veronica; Vo, Thanh-Trang; Fruman, David A.

    2015-01-01

    The PI3K/AKT/mTOR axis promotes survival and is a frequently mutated pathway in cancer. Yet, inhibitors targeting this pathway are insufficient to induce cancer cell death as single agents in some contexts, including diffuse large B cell lymphoma (DLBCL). In these situations, combinations with inhibitors targeting BCL-2 survival proteins (ABT-199 and ABT-263) may hold potential. Indeed, studies have demonstrated marked synergy in contexts where PI3K/mTOR inhibitors suppress expression of the pro-survival protein, MCL-1. In this study, we use BH3 profiling to confirm that BCL-2 and BCL-XL support survival following PI3K pathway inhibition, and that the dual PI3K/mTOR inhibitor BEZ235 strongly synergizes with BCL-2 antagonists in DLBCL. However, we identify an alternative mechanism of synergy between PI3K/mTOR and BCL-2 inhibitors, independent of MCL-1 down-regulation. Instead, we show that suppression of AKT activation by BEZ235 can induce the mitochondrial accumulation of pro-apoptotic BAD and BIM, and that expression of a constitutively active form of AKT prevents sensitization to BCL-2 antagonism. Thus, our work identifies an additional mechanism of synergy between PI3K pathway inhibitors and BCL-2 antagonists that strengthens the rationale for testing this combination in DLBCL. PMID:26460954

  15. Investigation on treatment strategy, prognostic factors, and risk factors for early death in elderly Taiwanese patients with diffuse large B-cell lymphoma

    PubMed Central

    Cho, Shih-Feng; Liu, Yi-Chang; Hsiao, Hui-Hua; Huang, Chiung-Tang; Tsai, Yu-Fen; Wang, Hui-Ching; Lin, Sheng-Fung; Liu, Ta-Chih

    2017-01-01

    This study aimed to investigate the treatment strategy, prognostic factors, and risk factors of early death in elderly patients (age ≥ 65 years) with diffuse large B-cell lymphoma (DLBCL) in the rituximab era. Data from elderly patients diagnosed with DLBCL between 2008 and 2014 were collected for analysis. Patients who were younger and had a better performance status were more likely to receive intensive frontline treatment. The median progression-free survival (PFS) and overall survival were 15 and 21 months, respectively. Anthracycline-containing chemotherapy achieved a higher remission rate and showed a trend towards better overall survival but a higher risk of severe neutropenia. Multivariate analysis revealed that very old age (≥81 years), a high-risk age-adjusted international prognostic index (aaIPI) score, and bone marrow involvement were associated with poorer PFS and overall survival. Progression of lymphoma was the major cause of death in the study population. In addition, approximately 25% of patients died within 120 days of being diagnosed. The risk factors for early mortality included very old age, a high-risk aaIPI score, and bone marrow involvement. The appearance of symptoms or signs of tumour lysis syndrome at diagnosis was associated with a trend towards early death. PMID:28290477

  16. Control of translational activation by PIM kinase in activated B-cell diffuse large B-cell lymphoma confers sensitivity to inhibition by PIM447

    PubMed Central

    Peters, Tara L.; Li, Lingxiao; Tula-Sanchez, Ana A.; Pongtornpipat, Praechompoo; Schatz, Jonathan H.

    2016-01-01

    The PIM family kinases promote growth and survival of tumor cells and are expressed in a wide variety of human cancers. Their potential as therapeutic targets, however, is complicated by overlapping activities with multiple other pathways and remains poorly defined in most clinical scenarios. Here we explore activity of the new pan-PIM inhibitor PIM447 in a variety of lymphoid-derived tumors. We find strong activity in cell lines derived from the activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL). Sensitive lines show lost activation of the mTORC1 signaling complex and subsequent lost activation of cap-dependent protein translation. In addition, we characterize recurrent PIM1 protein-coding mutations found in DLBCL clinical samples and find most preserve the wild-type protein's ability to protect cells from apoptosis but do not bypass activity of PIM447. Pan-PIM inhibition therefore may have an important role to play in the therapy of selected ABC-DLBCL cases. PMID:27556513

  17. The prognostic value of immunohistochemical subtyping in Chinese patients with de novo diffuse large B-cell lymphoma undergoing CHOP or R-CHOP treatment.

    PubMed

    Xia, Zu-Guang; Xu, Zi-Zhen; Zhao, Wei-Li; Zhao, Shu-Qing; Ding, Fei; Chen, Yu; Chen, Qiu-Sheng; Zheng, Yu; Zhu, Qi; Hu, Jun-Pei; Shen, Zhi-Xiang; Li, Jun-Min

    2010-02-01

    Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with recognised variability in molecular aetiology and clinical outcome. Though the use of agents such as rituximab significantly improves outcome, intrinsic genetic and morphological factors greatly affect the response to treatment. The objective of this study was to evaluate the prognostic value of immunohistochemical subtyping and the International Prognostic Index (IPI) for predicting treatment outcome in Chinese DLBCL patients. We followed 108 cases of DLBCL and performed prognostic analyses based on molecular subtyping of the disease through immunostaining of tissue samples. The use of rituximab conferred a clinical benefit to DLBCL patients regardless of disease subtype. Importantly, this treatment regimen also improved outcomes in patients with the non-germinal centre B-cell-like (GCB) DLBCL subtype, frequently associated with poorer prognosis. Our results suggest that IPI was the best tool for the prediction of treatment outcome in our patient cohort, regardless of treatment regimen. Furthermore, the use of rituximab alongside classical chemotherapy regimens can improve the outcomes for DLBCL patients who exhibit both GCB and non-GCB subtypes of the disease.

  18. Outcomes of diffuse large B-cell lymphoma patients relapsing after autologous stem cell transplantation: an analysis of patients included in the CORAL study.

    PubMed

    Van Den Neste, E; Schmitz, N; Mounier, N; Gill, D; Linch, D; Trneny, M; Bouadballah, R; Radford, J; Bargetzi, M; Ribrag, V; Dührsen, U; Ma, D; Briere, J; Thieblemont, C; Bachy, E; Moskowitz, C H; Glass, B; Gisselbrecht, C

    2017-02-01

    In the CORAL study, 255 chemosensitive relapses with diffuse large B-cell lymphoma (DLBCL) were consolidated with autologous stem cell transplantation (ASCT), and 75 of them relapsed thereafter. The median time between ASCT and progression was 7.1 months. The median age was 56.1 years; tertiary International Prognosis Index (tIPI) observed at relapse was 0-2 in 71.6% of the patients and >2 in 28.4%. The overall response rate to third-line chemotherapy was 44%. The median overall survival (OS) was 10.0 months (median follow-up: 32.8 months). Thirteen patients received an allogeneic SCT, and three a second ASCT. The median OS was shorter among patients who relapsed <6 months (5.7 months) compared with those relapsing ⩾12 months after ASCT (12.6 months, P=0.0221). The median OS in patients achieving CR, PR or no response after the third-line regimen was 37.7 (P<0.0001), 10.0 (P=0.03) and 6.3 months, respectively. The median OS varied according to tIPI: 0-2: 12.6 months and >2: 5.3 months (P=0.0007). In multivariate analysis, tIPI >2, achievement of response and remission lasting <6 months predicted the OS. This report identifies the prognostic factors for DLBCL relapsing after ASCT and thus helps to select patients for experimental therapy.

  19. A strong host response and lack of MYC expression are characteristic for diffuse large B cell lymphoma transformed from nodular lymphocyte predominant Hodgkin lymphoma

    PubMed Central

    Schuhmacher, Bianca; Rengstl, Benjamin; Döring, Claudia; Bein, Julia; Newrzela, Sebastian; Brunnberg, Uta; Kvasnicka, Hans Michael; Vornanen, Martine; Küppers, Ralf; Hansmann, Martin-Leo; Hartmann, Sylvia

    2016-01-01

    Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent lymphoma, but can transform into diffuse large B cell lymphoma (DLBCL), showing a more aggressive clinical behavior. Little is known about these cases on the molecular level. Therefore, the aim of the present study was to characterize DLBCL transformed from NLPHL (LP-DLBCL) by gene expression profiling (GEP). GEP revealed an inflammatory signature pinpointing to a specific host response. In a coculture model resembling this host response, DEV tumor cells showed an impaired growth behavior. Mechanisms involved in the reduced tumor cell proliferation included a downregulation of MYC and its target genes. Lack of MYC expression was also confirmed in 12/16 LP-DLBCL by immunohistochemistry. Furthermore, CD274/PD-L1 was upregulated in DEV tumor cells after coculture with T cells or monocytes and its expression was validated in 12/19 cases of LP-DLBCL. Thereby, our data provide new insights into the pathogenesis of LP-DLBCL and an explanation for the relatively low tumor cell content. Moreover, the findings suggest that treatment of these patients with immune checkpoint inhibitors may enhance an already ongoing host response in these patients. PMID:27708232

  20. Protein kinase C-associated kinase is required for NF-kappaB signaling and survival in diffuse large B-cell lymphoma cells.

    PubMed

    Kim, Sang-Woo; Oleksyn, David W; Rossi, Randall M; Jordan, Craig T; Sanz, Ignacio; Chen, Luojing; Zhao, Jiyong

    2008-02-01

    Diffuse large B-cell lymphoma (DLBCL) is an aggressive and the most common type of non-Hodgkin lymphoma. Despite recent advances in treatment, less than 50% of the patients are cured with current multiagent chemotherapy. Abnormal NF-kappaB activity not only contributes to tumor development but also renders cancer cells resistant to chemotherapeutic agents. Identifying and targeting signaling molecules that control NF-kappaB activation in cancer cells may thus yield more effective therapy for DLBCL. Here, we show that while overexpression of protein kinase C-associated kinase (PKK) activates NF-kappaB signaling in DLBCL cells, suppression of PKK expression inhibits NF-kappaB activity in these cells. In addition, we show that NF-kappaB activation induced by B cell-activating factor of tumor necrosis factor family (BAFF) in DLBCL cells requires PKK. Importantly, we show that knockdown of PKK impairs the survival of DLBCL cells in vitro and inhibits tumor growth of xenografted DLBCL cells in mice. Suppression of PKK expression also sensitizes DLBCL cells to treatment with chemotherapeutic agents. Together, these results indicate that PKK plays a pivotal role in the survival of human DLBCL cells and represents a potential target for DLBCL therapy.

  1. Higher incidence of the SNP Met 788 Ile in the coding region of A20 in diffuse large B cell lymphomas.

    PubMed

    Wenzl, Kerstin; Hofer, Sybille; Troppan, Katharina; Lassnig, Markus; Steinbauer, Elisabeth; Wiltgen, Marco; Zulus, Barbara; Renner, Wilfried; Beham-Schmid, Christine; Neumeister, Peter; Deutsch, Alexander

    2016-04-01

    Genetic alterations causing constitutive activation of the nuclear factor kappa B (NF-κB) signaling pathway has been associated with the development of lymphomas. A20 (TNFAIP3) is a key regulator of NF-κB signaling. Its suppressor functions are often inactivated by deletions and/or mutations in various hematologic malignancies. Since we recently found the rs143002189 polymorphism in the A20 loci in our multiple myeloma samples, we further investigated this polymorphism in different lymphoid neoplasias. For this purpose, we tested 479 cases of the most common B cell malignancies for the presence of the rs143002189 polymorphism. We found a significant higher occurrence of the rs143002189 polymorphism in diffuse large B cell lymphoma (DLBCL) compared to non-neoplastic controls and other types of B cell malignancies. Furthermore, structure analyses of the mutated A20 protein led to the assumption that the new steric interaction within the protein is responsible for a reduced or inactivated A20 protein. Our data indicates that in a significant fraction of patients, rs143002189 might contribute to the development of DLBCL.

  2. Synergistic activity of Card11 mutant and Bcl6 in the development of diffuse large B-cell lymphoma in a mouse model.

    PubMed

    Takahara, Taishi; Matsuo, Keitaro; Seto, Masao; Nakamura, Shigeo; Tsuzuki, Shinobu

    2016-11-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma; it derives from germinal center B cells. Although DLBCL harbors many genetic alterations, synergistic roles between such alterations in the development of lymphoma are largely undefined. We previously established a mouse model of lymphoma by transplanting gene-transduced germinal center B cells into mice. Here, we chose one of the frequently mutated genes in DLBCL, Card11 mutant, to explore its possible synergy with other genes, using our lymphoma model. Given that BCL6 and BCL2 expression and/or function are often deregulated in human lymphoma, we examined the possible synergy between Card11, Bcl6, and Bcl2. Germinal center B cells were induced in vitro, transduced with Card11 mutant, Bcl6, and Bcl2, and transplanted. Mice rapidly developed lymphomas, with exogenously transduced Bcl2 being dispensable. Although some mice developed lymphoma in the absence of transduced Bcl6, the absence was compensated by elevated expression of endogenous Bcl6. Additionally, the synergy between Card11 mutant and Bcl6 in the development of lymphoma was confirmed by the fact that the combination of Card11 mutant and Bcl6 caused lymphoma or death significantly earlier and with higher penetrance than Card11 mutant or Bcl6 alone. Lymphoma cells expressed interferon regulatory factor 4 and PR domain 1, indicating their differentiation toward plasmablasts, which characterize activated B cell-like DLBCL that represents a clinically aggressive subtype in humans. Thus, our mouse model provides a versatile tool for studying the synergistic roles of altered genes underlying lymphoma development.

  3. Primary Cutaneous Diffuse Large B-Cell Lymphoma With a MYC-IGH Rearrangement and Gain of BCL2: Expanding the Spectrum of MYC/BCL2 Double-Hit Lymphomas.

    PubMed

    Testo, Natalia; Olson, Luke C; Subramaniyam, Shivakumar; Hanson, Ty; Magro, Cynthia M

    2016-10-01

    Aggressive extracutaneous B-cell lymphomas span the various stages of B-cell ontogeny and include B-cell lymphoblastic lymphoma, Burkitt lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Diffuse large B-cell lymphomas represent the most common histologic subtype of non-Hodgkin lymphomas, comprising 30% of adult non-Hodgkin lymphomas in the United States. A distinctive form of diffuse large B-cell lymphoma is the double-hit lymphoma, with most cases exhibiting a combined MYC and BCL2 rearrangement, leading some hematopathologists to propose the term MYC/BCL2 lymphoma. More recently, MYC rearrangement with multiple copies/gain of BCL2 or multiple copies/gain of MYC with a BCL2 rearrangement have been described and exhibit a very similar clinical course to conventional double-hit lymphomas. We report the seventh case of diffuse large B-cell lymphoma exhibiting this distinct cytogenetic abnormality and the first reported case in the skin. The patient's clinical course was aggressive, succumbing to disease 18 months after his initial presentation.

  4. Joint derivation method for determining optical properties based on steady-state spatially resolved diffuse reflectance measurement at small source-detector separations and large reduced albedo range: theory and simulation.

    PubMed

    Shi, Zhenzhi; Fan, Ying; Zhao, Huijuan; Xu, Kexin

    2012-06-01

    Accurate determination of the optical properties (the absorption coefficient μ(a) and the reduced scattering coefficient μ(s) (')) of tissues is very important in a variety of diagnostic and therapeutic procedures. Optical diffusion theory is frequently used as the forward model for describing the photon transfer in media with large reduced albedos (a(')) and in large source-detector separations (SDS). Several other methods (PN approximation, hybrid diffusion-P3 approximation) have also been published that describe photon transfer in media with low a(') or small SDSs. We studied the theoretical models for the steady-state spatially resolved diffuse reflectance measurement to accurately determine μ(a) and μ(s) (') at large a(') range but small SDSs. Instead of using a single model, a joint derivation method is proposed. The developed method uses one of the best aforementioned theoretical methods separately in five ranges of a(') determined from several forward models. In the region of small SDSs (the range between 0.4 and 8 mm) and large a(') range (between 0.5 and 0.99), the best theoretical derivation model was determined. The results indicate that the joint derivation method can improve the derivation accuracy and that a(') range can be determined by the steady-state spatially resolved diffuse reflectance measurement.

  5. Activation of the STAT3 Signaling Pathway Is Associated With Poor Survival in Diffuse Large B-Cell Lymphoma Treated With R-CHOP

    PubMed Central

    Huang, Xin; Meng, Bin; Iqbal, Javeed; Ding, B. Belinda; Perry, Anamarija M.; Cao, Wenfeng; Smith, Lynette M.; Bi, Chengfeng; Jiang, Chunsun; Greiner, Timothy C.; Weisenburger, Dennis D.; Rimsza, Lisa; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elias; Braziel, Rita M.; Gascoyne, Randy D.; Cook, James R.; Tubbs, Raymond R.; Jaffe, Elaine S.; Armitage, James O.; Vose, Julie M.; Staudt, Louis M.; McKeithan, Timothy W.; Chan, Wing C.; Ye, B. Hilda; Fu, Kai

    2013-01-01

    Purpose We previously reported that constitutive STAT3 activation is a prominent feature of the activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL). In this study, we investigated whether STAT3 activation can risk stratify patients with DLBCL. Patients and Methods By an immunohistochemical method, we investigated phosphotyrosine STAT3 (PY-STAT3) expression from 185 patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Cell line-based siRNA experiments were also performed to generate an 11-gene, PY-STAT3 activation signature, which was used to study a previously published cohort of 222 patients with DLBCL. The STAT3 activation status determined by these two methods and by STAT3 mRNA levels were then correlated with survival. Results PY-STAT3 was detected in 37% of DLBCL and enriched in ABC-DLBCL cases (P = .03). PY-STAT3 positivity significantly correlated with poor overall survival (OS; P = .01) and event-free survival (EFS; P = .006). Similar observations were made for high levels of STAT3 mRNA. In multivariable analysis, PY-STAT3 status (P = .02), International Prognostic Index (P = .02), and BCL2 expression (P = .046) were independent prognosticators of OS in this cohort. Among the cell-of-origin subgroups, PY-STAT3 was associated with poor EFS among non–germinal center B-cell DLBCL cases only (P = .027). Similarly, the 11-gene STAT3 activation signature correlated with poor survival in the entire DLBCL cohort (OS, P < .001; EFS, P < .001) as well as the ABC-DLBCL subgroup (OS, P = .029; EFS, P = .025). Conclusion STAT3 activation correlated with poor survival in patients with DLBCL treated with R-CHOP, especially those with tumors of the ABC-DLBCL subtype. PMID:24220563

  6. Concurrent Expression of MYC and BCL2 in Diffuse Large B-Cell Lymphoma Treated With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

    PubMed Central

    Johnson, Nathalie A.; Slack, Graham W.; Savage, Kerry J.; Connors, Joseph M.; Ben-Neriah, Susana; Rogic, Sanja; Scott, David W.; Tan, King L.; Steidl, Christian; Sehn, Laurie H.; Chan, Wing C.; Iqbal, Javeed; Meyer, Paul N.; Lenz, Georg; Wright, George; Rimsza, Lisa M.; Valentino, Carlo; Brunhoeber, Patrick; Grogan, Thomas M.; Braziel, Rita M.; Cook, James R.; Tubbs, Raymond R.; Weisenburger, Dennis D.; Campo, Elias; Rosenwald, Andreas; Ott, German; Delabie, Jan; Holcroft, Christina; Jaffe, Elaine S.; Staudt, Louis M.; Gascoyne, Randy D.

    2012-01-01

    Purpose Diffuse large B-cell lymphoma (DLBCL) is curable in 60% of patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MYC translocations, with or without BCL2 translocations, have been associated with inferior survival in DLBCL. We investigated whether expression of MYC protein, with or without BCL2 protein expression, could risk-stratify patients at diagnosis. Patients and Methods We determined the correlation between presence of MYC and BCL2 proteins by immunohistochemistry (IHC) with survival in two independent cohorts of patients with DLBCL treated with R-CHOP. We further determined if MYC protein expression correlated with high MYC mRNA and/or presence of MYC translocation. Results In the training cohort (n = 167), MYC and BCL2 proteins were detected in 29% and 44% of patients, respectively. Concurrent expression (MYC positive/BCL2 positive) was present in 21% of patients. MYC protein correlated with presence of high MYC mRNA and MYC translocation (both P < .001), but the latter was less frequent (both 11%). MYC protein expression was only associated with inferior overall and progression-free survival when BCL2 protein was coexpressed (P < .001). Importantly, the poor prognostic effect of MYC positive/BCL2 positive was validated in an independent cohort of 140 patients with DLBCL and remained significant (P < .05) after adjusting for presence of high-risk features in a multivariable model that included elevated international prognostic index score, activated B-cell molecular subtype, and presence of concurrent MYC and BCL2 translocations. Conclusion Assessment of MYC and BCL2 expression by IHC represents a robust, rapid, and inexpensive approach to risk-stratify patients with DLBCL at diagnosis. PMID:22851565

  7. Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma.

    PubMed

    Havas, Aaron P; Rodrigues, Kameron B; Bhakta, Anvi; Demirjian, Joseph A; Hahn, Seongmin; Tran, Jack; Scavello, Margarethakay; Tula-Sanchez, Ana A; Zeng, Yi; Schmelz, Monika; Smith, Catharine L

    2016-12-01

    Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with a variety of other drugs. However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, cell-type specific mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines. In the current study, we demonstrate that cell lines sensitive to the cytotoxic effects of HDACi undergo early mitotic arrest prior to apoptosis. In contrast, HDACi-resistant cell lines complete mitosis after a short delay and arrest in G1. To force mitotic arrest in HDACi-resistant cell lines, we used low dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity. Belinostat curtails vincristine-induced mitotic arrest and triggers a strong apoptotic response associated with downregulated MCL-1 expression and upregulated BIM expression. Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression. Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population. Our study demonstrates that vincristine sensitizes DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevents polyploidy that could cause vincristine resistance. Our findings provide a rationale for using low dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.

  8. p27KIP1 is abnormally expressed in Diffuse Large B-Cell Lymphomas and is associated with an adverse clinical outcome

    PubMed Central

    Sáez, Al; Sánchez, E; Sánchez-Beato, M; Cruz, M A; Chacón, I; Muñoz, E; Camacho, F I; Martínez-Montero, J C; Mollejo, M; Garcia, J F; Piris, M A

    1999-01-01

    Cell cycle progression is regulated by the combined action of cyclins, cyclin-dependent kinases (CDKs), and CDK-inhibitors (CDKi), which are negative cell cycle regulators. p27KIP1 is a CDKi key in cell cycle regulation, whose degradation is required for G1/S transition. In spite of the absence of p27KIP1 expression in proliferating lymphocytes, some aggressive B-cell lymphomas have been reported to show an anomalous p27KIP1 staining. We analysed p27KIP1 expression in a series of Diffuse Large B-cell Lymphoma (DLBCL), correlating it with the proliferative index and clinical outcome, to characterize the implications of this anomalous staining in lymphomagenesis in greater depth. For the above mentioned purposes, an immunohistochemical technique in paraffin-embedded tissues was employed, using commercially available antibodies, in a series of 133 patients with known clinical outcomes. Statistical analysis was performed in order to ascertain which clinical and molecular variables may influence outcome, in terms of disease-free survival (DFS) and overall survival (OS). The relationships between p27KIP1 and MIB-1 (Ki-67) were also tested. An abnormally high expression of p27KIP1 was found in lymphomas of this type. The overall correlation between p27KIP1 and MIB-1 showed there to be no significant relationship between these two parameters, this differing from observations in reactive lymphoid and other tissues. Analysis of the clinical relevance of these findings showed that a high level of p27KIP1 expression in this type of tumour is an adverse prognostic marker, in both univariate and multivariate analysis. These results show that there is abnormal p27KIP1 expression in DLBCL, with adverse clinical significance, suggesting that this anomalous p27KIP1 protein may be rendered non-functional through interaction with other cell cycle regulator proteins. © 1999 Cancer Research Campaign PMID:10424746

  9. Loss of function mutations in PTPN6 promote STAT3 deregulation via JAK3 kinase in diffuse large B-cell lymphoma.

    PubMed

    Demosthenous, Christos; Han, Jing Jing; Hu, Guangzhen; Stenson, Mary; Gupta, Mamta

    2015-12-29

    PTPN6 (SHP1) is a tyrosine phosphatase that negatively controls the activity of multiple signaling pathways including STAT signaling, however role of mutated PTPN6 is not much known. Here we investigated whether PTPN6 might also be a potential target for diffuse large B cell lymphoma (DLBCL) and performed Sanger sequencing of the PTPN6 gene. We have identified missense mutations within PTPN6 (N225K and A550V) in 5% (2/38) of DLBCL tumors. Site directed mutagenesis was performed to mutate wild type (WT) PTPN6 and stable cell lines were generated by lentiviral transduction of PTPN6(WT), PTPN6(N225K) and PTPN6(A550V) constructs, and effects of WT or mutated PTPN6 on STAT3 signaling were analyzed. WT PTPN6 dephosphorylated STAT3, but had no effect on STAT1, STAT5 or STAT6 phosphorylation. Both PTPN6 mutants were unable to inhibit constitutive, as well as cytokines induced STAT3 activation. Both PTPN6 mutants also demonstrated reduced tyrosine phosphatase activity and exhibited enhanced STAT3 transactivation activity. Intriguingly, a lack of direct binding between STAT3 and WT or mutated PTPN6 was observed. However, compared to WT PTPN6, cells expressing PTPN6 mutants exhibited increased binding between JAK3 and PTPN6 suggesting a more dynamic interaction of PTPN6 with upstream regulators of STAT3. Consistent with this notion, both the mutants demonstrated increased resistance to JAK3 inhibitor, WHIP-154 relative to WT PTPN6. Overall, this is the first study, which demonstrates that N225K and A550V PTPN6 mutations cause loss-of-function leading to JAK3 mediated deregulation of STAT3 pathway and uncovers a mechanism that tumor cells can use to control PTPN6 substrate specificity.

  10. PATZ1 expression correlates positively with BAX and negatively with BCL6 and survival in human diffuse large B cell lymphomas

    PubMed Central

    Valentino, Elena; Vitiello, Michela; Luciano, Antonio; Palma, Giuseppe; Arra, Claudio; Mantia, Elvira La; Panico, Luigi; Tenneriello, Valentina; Pinto, Antonello; Frigeri, Ferdinando; Capobianco, Gaetana; Botti, Gerardo; Cerchia, Laura; De Chiara, Annarosaria; Fedele, Monica

    2016-01-01

    Non-Hodgkin lymphomas (NHLs) include a heterogeneous group of diseases, which differ in both cellular origin and clinical behavior. Among the aggressive malignancies of this group, the diffuse large B-cell lymphomas (DLBCLs) are the most frequently observed. They are themselves clinically and molecularly heterogeneous and have been further sub-divided in three sub-types according to different cell of origin, mechanisms of oncogenesis and clinical outcome. Among them, the germinal center B-cell-like (GCB) derives from the germinal center and expresses the BCL6 oncogene. We have previously shown that Patz1-knockout mice develop B-cell neoplasias, suggesting a tumor suppressor role for PATZ1 in human NHLs. Here, by immunohistochemical analysis of a tissue-microarray including 170 NHLs, we found that PATZ1 nuclear expression is down-regulated in follicular lymphomas and DLBCLs. Moreover, consistent with our previous results showing a PATZ1-dependent regulation of BCL6 and BAX transcription, we show that low PATZ1 nuclear expression significantly correlates with high BCL6 expression, mainly in DLBCLs, and with low BAX expression, also considering separately follicular lymphomas and DLBCLs. Finally, by analyzing overall and progression-free survival in DLBCL patients that underwent rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, low levels of PATZ1 were significantly associated to a worst outcome and demonstrated an independent prognostic factor in multivariate analysis, including known prognostic factors of DLBCL, IPI score and cell of origin (GCB/non-GCB). Therefore, we propose PATZ1 as a new prognostic marker of DLBCLs, which may act as a tumor suppressor by enhancing apoptosis through inhibiting and enhancing transcription of BCL6 and BAX, respectively. PMID:27494852

  11. PATZ1 expression correlates positively with BAX and negatively with BCL6 and survival in human diffuse large B cell lymphomas.

    PubMed

    Franco, Renato; Scognamiglio, Giosuè; Valentino, Elena; Vitiello, Michela; Luciano, Antonio; Palma, Giuseppe; Arra, Claudio; La Mantia, Elvira; Panico, Luigi; Tenneriello, Valentina; Pinto, Antonello; Frigeri, Ferdinando; Capobianco, Gaetana; Botti, Gerardo; Cerchia, Laura; De Chiara, Annarosaria; Fedele, Monica

    2016-09-13

    Non-Hodgkin lymphomas (NHLs) include a heterogeneous group of diseases, which differ in both cellular origin and clinical behavior. Among the aggressive malignancies of this group, the diffuse large B-cell lymphomas (DLBCLs) are the most frequently observed. They are themselves clinically and molecularly heterogeneous and have been further sub-divided in three sub-types according to different cell of origin, mechanisms of oncogenesis and clinical outcome. Among them, the germinal center B-cell-like (GCB) derives from the germinal center and expresses the BCL6 oncogene. We have previously shown that Patz1-knockout mice develop B-cell neoplasias, suggesting a tumor suppressor role for PATZ1 in human NHLs. Here, by immunohistochemical analysis of a tissue-microarray including 170 NHLs, we found that PATZ1 nuclear expression is down-regulated in follicular lymphomas and DLBCLs. Moreover, consistent with our previous results showing a PATZ1-dependent regulation of BCL6 and BAX transcription, we show that low PATZ1 nuclear expression significantly correlates with high BCL6 expression, mainly in DLBCLs, and with low BAX expression, also considering separately follicular lymphomas and DLBCLs. Finally, by analyzing overall and progression-free survival in DLBCL patients that underwent rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, low levels of PATZ1 were significantly associated to a worst outcome and demonstrated an independent prognostic factor in multivariate analysis, including known prognostic factors of DLBCL, IPI score and cell of origin (GCB/non-GCB). Therefore, we propose PATZ1 as a new prognostic marker of DLBCLs, which may act as a tumor suppressor by enhancing apoptosis through inhibiting and enhancing transcription of BCL6 and BAX, respectively.

  12. Stromal immune infiltration in HIV-related diffuse large B-cell lymphoma is associated with HIV disease history and patient survival

    PubMed Central

    CHAO, Chun; XU, Lanfang; SILVERBERG, Michael J; MARTÍNEZ-MAZA, Otoniel; CHEN, Lie-Hong; CASTOR, Brandon; ABRAMS, Donald I; ZHA, Hongbin D; HAQUE, Reina; SAID, Jonathan

    2015-01-01

    Objective Understanding tumor microenvironment and its impact on prognosis of HIV-related lymphomas may provide insight into novel therapeutic strategies. Design We characterized the relationship between infiltrating immune cells with tumor characteristics, HIV disease history and survival in 80 HIV-related diffuse large B-cell lymphoma (DLBCL) patients diagnosed in the era of combined antiretroviral therapy (1996–2007) at Kaiser Permanente (KP) California. Eighty HIV-unrelated DLBCL patients were included for comparison. Methods Data on patients’ clinical history were obtained from KP’s electronic health records. The density of stromal CD4+, CD8+ and FOXP3+ T cells and CD68+ macrophages, as well as tumor molecular characteristics were examined using immunohistochemistry. The associations between stromal immune infiltration and patient’s clinical history or tumor characteristics were examined using Kruskal Wallis tests or Peasrons’ correlation coefficient. The effect of stromal immune infiltration on two-year mortality was evaluated in multivariable logistic regression. Results Compared to HIV-unrelated DLBCL, patients with HIV-related DLBCL had significantly reduced stromal CD4+ and FOXP3+ T cells, but increased density of macrophages. Increased density of stromal macrophages was correlated with lower circulating CD4 cell count at DLBCL diagnosis. Tumor molecular characteristics, including BCL6, p53 and cMYC expression, but not EBV infection status, were significantly correlated with stromal immune infiltration, particularly FOXP3+ T cells. A higher density of infiltrating CD8+ T cell was significantly associated with reduced mortality in HIV-related DLBCL patients [odds ratio=0.30 (0.09–0.97) for ≥25% vs. <10%]. Conclusion These data provide evidence for the prognostic significance of cytotoxic T cells in determining outcomes of HIV-related lymphoma. PMID:26355571

  13. Excellent Outcomes and Lack of Prognostic Impact of Cell of Origin for Localized Diffuse Large B-cell Lymphoma in the Rituximab Era

    PubMed Central

    Kumar, Anita; Lunning, Matthew A.; Zhang, Zhigang; Migliacci, Jocelyn C.; Moskowitz, Craig H.; Zelenetz, Andrew D.

    2015-01-01

    Summary Therapeutic options for limited-stage diffuse large B cell lymphoma (DLBCL) include short- or full-course R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) +/- radiotherapy. The optimal treatment remains unclear. The prognostic value of cell-of-origin (COO) in early stage DLBCL is unknown. Patients with limited-stage DLBCL (stage I or stage II, non-bulky) treated with R-CHOP +/- involved field radiotherapy (IFRT) from 1999 – 2012 were included. COO by the Hans algorithm was analysed in a subset of patients. Of 261 patients, 30% were stage I (N=82), 37% Stage IE (N=96), <1% stage IXEE (N=1), 18% stage II (N=46) and 14% Stage IIE (N=37). The stage-modified IPI stratified patients into prognostically relevant groups. There was no significant difference in progression-free survival (PFS) or overall survival (OS) for patients in the germinal centre B-cell-like (GCB; n=65) and non-GCB cohorts (n=22). Seventeen patients received R-CHOP x 3-4 cycles (Arm A), 147 received R-CHOP x 3-4 cycles + IFRT (Arm B), 48 received R-CHOP x6 cycles (Arm C), and 50 received R-CHOP x6 cycles +IFRT (Arm D). The outcomes were excellent, with 5-year PFS of 82% and 5-year OS of 93%, and were similar across the 4 treatment groups. In the rituximab era, outcomes for limited-stage DLBCL, regardless of treatment approach, were excellent. Baseline COO was not a significant prognostic factor in patients treated with short-course R-CHOP + IFRT. PMID:26456939

  14. Prediction of Central Nervous System Relapse of Diffuse Large B-Cell Lymphoma Using Pretherapeutic [18F]2-Fluoro-2-Deoxyglucose (FDG) Positron Emission Tomography/Computed Tomography

    PubMed Central

    Song, Yoo Sung; Lee, Won Woo; Lee, Jong Seok; Kim, Sang Eun

    2015-01-01

    Abstract Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare complication, but has a poor prognosis with unknown pathophysiology. Recent trials of CNS prophylaxis have shown to be ineffective, despite patient's selection using several known clinical risk factors. In this study, the authors evaluated the value of pretreatment [18F]2-Fluoro-2-deoxyglucose positron emission tomography in predicting CNS relapse in DLBCL patients. The authors analyzed 180 pathologically confirmed DLBCL patients, retrospectively. Patients underwent [18F]2-Fluoro-2-deoxyglucose positron emission tomography/computed tomography before first line rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone therapy. Clinical characteristics were evaluated and total lesion glycolysis (TLG) with a threshold margin of 50% was calculated. Among age, sex, Ann Arbor stage, International Prognostic Index, revised International Prognostic Index, high serum lactate dehydrogenase level, presence of B symptoms, bulky disease (≥10 cm), extranodal lesion involvement, bone marrow involvement, high metabolic tumor volume ( >450 mL), and high TLG50 (>2000), the high TLG50 was the only significant prognostic factor for predicting CNS relapse in a multivariate analysis (P = 0.04). Kaplan–Meir survival analysis between high TLG50 (>2000) and low TLG50 (≤2000) groups revealed significantly different mean progression free survival (PFS) of 1317.2 ± 134.3 days and 1968.6 ± 18.3 days, respectively (P < 0.001). High TLG50 on [18F]2-Fluoro-2-deoxyglucose positron emission tomography/computed tomography is the most significant predictor of CNS relapse in un-treated DLBCL patients. PMID:26554808

  15. Prediction of survival by applying current prognostic models in diffuse large B-cell lymphoma treated with R-CHOP followed by autologous transplantation

    PubMed Central

    Kim, Sung-Yong; Kim, Inho; Kim, Yeo-Kyeoung; Kim, Jeong-A; Kim, Yang Soo; Lee, Ho Sup; Park, Jinny; Kim, Seok Jin; Shim, Hyeok; Eom, Hyeon Seok; Park, Byeong-Bae; Lee, Junglim; Park, Sung Kyu; Cheong, June-Won; Park, Keon Woo

    2015-01-01

    Background Among the currently available prognostic models for diffuse large B-cell lymphoma (DLBCL), we investigated to determine which is most adoptable for DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) followed by upfront autologous stem cell transplantation (auto-SCT). Methods We retrospectively evaluated survival differences among risk groups based on the International Prognostic Index (IPI), the age-adjusted IPI (aaIPI), the revised IPI (R-IPI), and the National Comprehensive Cancer Network IPI (NCCN-IPI) at diagnosis in 63 CD20-positive DLBCL patients treated with R-CHOP followed by upfront auto-SCT. Results At the time of auto-SCT, 74.6% and 25.4% of patients had achieved complete remission and partial remission after R-CHOP, respectively. As a whole, the 5-year overall (OS) and progression-free survival (PFS) rates were 78.8% and 74.2%, respectively. The 5-year OS and PFS rates according to the IPI, aaIPI, R-IPI, and NCCN-IPI did not significantly differ among the risk groups for each prognostic model (P-values for OS: 0.255, 0.337, 0.881, and 0.803, respectively; P-values for PFS: 0.177, 0.904, 0.295, and 0.609, respectively). Conclusion There was no ideal prognostic model among those currently available for CD20-positive DLBCL patients treated with R-CHOP followed by upfront auto-SCT. PMID:26457283

  16. High total metabolic tumor volume in PET/CT predicts worse prognosis in diffuse large B cell lymphoma patients with bone marrow involvement in rituximab era.

    PubMed

    Song, Moo-Kon; Yang, Deok-Hwan; Lee, Gyeong-Won; Lim, Sung-Nam; Shin, Seunghyeon; Pak, Kyoung June; Kwon, Seong Young; Shim, Hye Kyung; Choi, Bong-Hoi; Kim, In-Suk; Shin, Dong-Hoon; Kim, Seong-Geun; Oh, So-Yeon

    2016-03-01

    Bone marrow involvement (BMI) in diffuse large B cell lymphoma (DLBCL) was naively regarded as an adverse clinical factor. However, it has been unknown which factor would separate clinical outcomes in DLBCL patients with BMI. Recently, metabolic tumor volume (MTV) on positron emission tomography/computed tomography (PET/CT) was suggested to predict prognosis in several lymphoma types. Therefore, we investigated whether MTV would separate the outcomes in DLBCL patients with BMI. MTV on PET/CT was defined as an initial tumor burden as target lesion ≥ standard uptake value, 2.5 in 107 patients with BMI. Intramedullary (IM) MTV was defined as extent of BMI and total MTV was as whole tumor burden. 260.5 cm(3) and 601.2 cm(3) were ideal cut-off values for dividing high and low MTV status in the IM and total lymphoma lesions in Receiver Operating Curve analysis. High risk NCCN-IPI (p<0.001, p<0.001), bulky disease (p=0.011, p=0.005), concordant subtype (p=0.025, p=0.029), high IM MTV status (p<0.001, p<0.001), high total MTV status (p<0.001, p<0.001), and ≥ 2CAs in BM (p=0.037, p=0.033) were significantly associated with progression-free survival (PFS) and overall survival (OS) than other groups. In multivariate analysis, high risk NCCN-IPI (PFS, p=0.006; OS, p=0.013), concordant subtype (PFS, p=0.005; OS, p=0.007), and high total MTV status (PFS, p<0.001; OS, p<0.001) had independent clinical impacts. MTV had prognostic significances for survivals in DLBCL with BMI.

  17. Outcomes and Effect of Radiotherapy in Patients With Stage I or II Diffuse Large B-Cell Lymphoma: A Surveillance, Epidemiology, and End Results Analysis

    SciTech Connect

    Ballonoff, Ari Rusthoven, Kyle E.; Schwer, Amanda; McCammon, Robert; Kavanagh, Brian; Bassetti, Michael; Newman, Francis; Rabinovitch, Rachel

    2008-12-01

    Purpose: To assess disease-specific survival (DSS), overall survival (OS), and the effect of radiotherapy (RT) in patients with localized diffuse large B-cell lymphoma (DLBCL). Patients and Methods: The Surveillance, Epidemiology, and End Results database was queried for all patients diagnosed with Stage I, IE, II, or IIE DLBCL between 1988 and 2004. The analyzable data included gender, age, race, stage, presence of extranodal disease, and RT administration. Patients who had died or were lost to follow-up within 6 months of diagnosis were excluded. Results: A total of 13,420 patients met the search criteria. Of these, 5,547 (41%) had received RT and 7,873 (59%) had not. RT was associated with a significant DSS (hazard ratio, 0.82, p <0.0001) and OS benefit that persisted during the 15 years of follow-up. Elderly patients, defined either as those >60 or >70 years old, had significantly improved DSS and OS associated with RT. On multivariate analysis, RT was significantly associated with increased DSS and OS. The 5-year DSS outcomes were highly variable among patient subsets, defined by age, stage, and extranodal disease (range for RT-treated patients, 70% for Stage II, age >60 years to 87% for Stage I, age {<=}60 years). Conclusion: This analysis presents the largest detailed data set of Stage I-II DLBCL patients. The results of our study have demonstrated that RT is associated with a survival advantage in patients with localized DLBCL, a benefit that extends to elderly patients. Outcomes for discrete patient subsets varied greatly. The development of tailored therapy according to the relapse risk is warranted, rather than uniform treatment of all early-stage DLBCL.

  18. UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma.

    PubMed

    Bedekovics, Tibor; Hussain, Sajjad; Feldman, Andrew L; Galardy, Paul J

    2016-03-24

    Gene expression profiling has identified 2 major subclasses of diffuse large B-cell lymphoma (DLBCL). Cases resembling germinal center (GC) B cells (GCB-DLBCL) generally occur in younger patients, have a distinct molecular pathophysiology, and have improved outcomes compared with those similar to activated post-GC cells (activated B-cell DLBCL). We previously found that the ubiquitin hydrolase UCH-L1 is frequently overexpressed in mature B-cell malignancies and is a potent oncogene in mice. The cause for its overexpression in lymphoma, and whether it impacts the outcome of patients with DLBCL is unknown. Here, we show that UCH-L1 reflects GC lineage in lymphoma and is an oncogenic biomarker of aggressive GCB-DLBCL. We find that UCH-L1 is specifically induced in GC B cells in mice and humans, and that its expression correlates highly with the GCB subtype in DLBCL. We also find that UCH-L1 cooperates with BCL6 in a mouse model of GC B-cell lymphoma, but not with the development of multiple myeloma derived from post-GC cells. Despite the typically good outcomes of GCB-DLBCL, increased UCHL1 identifies a subgroup with early relapses independent of MYC expression, suggesting biological diversity in this subset of disease. Consistent with this, forced Uchl1 overexpression had a substantial impact on gene expression in GC B cells including pathways of cell cycle progression, cell death and proliferation, and DNA replication. These data demonstrate a novel role for UCH-L1 outside of the nervous system and suggest its potential use as a biomarker and therapeutic target in DLBCL.

  19. Limited role of interim PET/CT in patients with diffuse large B-cell lymphoma treated with R-CHOP.

    PubMed

    Yoo, Changhoon; Lee, Dae Ho; Kim, Jeong Eun; Jo, Jungmin; Yoon, Dok Hyun; Sohn, Byeong Seok; Kim, Sang-We; Lee, Jung-Shin; Suh, Cheolwon

    2011-07-01

    Positron emission tomography (PET) has been found useful in monitoring response to treatment of malignant lymphoma. We investigated the ability of interim PET to monitor response to standard dose R-CHOP chemotherapy in chemotherapy-naïve patients with diffuse large B-cell lymphoma (DLBCL). Between March 2004 and April 2009, 155 DLBCL patients treated with R-CHOP and available for interim and post-treatment PET/CT were identified and included in this analysis. Response, progression-free survival (PFS), and overall survival (OS) were compared between interim PET/CT-negative and positive group, and among three patient groups which were categorized based on their interim and post-treatment PET/CT: those with early metabolic complete response (mCR), delayed mCR, and never mCR. Interim PET/CT-negative patients (n=100) showed superior CR rates to interim PET/CT-positive patients (n=55; 93% vs 62%, P<0.001). However, there was no difference in PFS (P=0.07) and OS (P=0.24) between interim PET/CT-negative and positive group. We categorized patients into three groups, with 100 (64%) in the early mCR group, 35 (23%) in the delayed mCR group, and 20 (13%) in the never mCR group. Early mCR and delayed mCR group did not differ significantly in PFS (P=0.84) or OS (P=0.20). However, the survival outcome in the never mCR group was significantly inferior to the combined early and delayed mCR group. The result from this study suggests that interim PET/CT might be an inappropriate tool for designing risk-adaptive therapy in chemotherapy-naïve DLBCL patients treated with R-CHOP. Prospective trials should be performed to clearly determine the role of interim PET/CT.

  20. Prognostic value of interim FDG-PET in R-CHOP-treated diffuse large B-cell lymphoma: Systematic review and meta-analysis.

    PubMed

    Adams, Hugo J A; Kwee, Thomas C

    2016-10-01

    This study aimed to systematically review and meta-analyze the prognostic value of interim (18)F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). MEDLINE and EMBASE were systematically searched for suitable studies. Included studies were methodologically appraised, and results were summarized both descriptively and meta-analytically. Nine studies, comprising a total of 996 R-CHOP-treated DLBCL patients, were included. Overall, studies were of moderate methodological quality. The area under the summary receiver operating curve (AUC) of interim FDG-PET in predicting treatment failure and death were 0.651 and 0.817, respectively. There was no heterogeneity in diagnostic odds ratios across available studies (I(2)=0.0%). At multivariable analysis, 2 studies reported interim FDG-PET to have independent prognostic value in addition to the International Prognostic Index (IPI) in predicting treatment failure, whereas 3 studies reported that this was not the case. One study reported interim FDG-PET to have independent prognostic value in addition to the IPI in predicting death, whereas 2 studies reported that this was not the case. In conclusion, interim FDG-PET in R-CHOP-treated DLBCL has some correlation with outcome, but its prognostic value is homogeneously suboptimal across studies and it has not consistently proven to surpass the prognostic potential of the IPI. Moreover, there is a lack of studies that compared interim FDG-PET to the recently developed and superior National Comprehensive Cancer Network-IPI. Therefore, at present there is no scientific base to support the clinical use of interim FDG-PET in R-CHOP-treated DLBCL.

  1. Diffuse large B-cell lymphoma solely involving bilateral adrenal glands and stomach: report of an extremely rare case with review of the literature.

    PubMed

    Wakabayashi, Mutsumi; Sekiguchi, Yasunobu; Shimada, Asami; Ichikawa, Kunimoto; Sugimoto, Keiji; Tomita, Shigeki; Izumi, Hiroshi; Nakamura, Noriko; Sawada, Tomohiro; Ohta, Yasunori; Komatsu, Norio; Noguchi, Masaaki

    2014-01-01

    A 60-year-old man complained of nausea, vomiting, decreased appetite, and a feeling of abdominal fullness in August 2013. Based on biopsy findings from an upper gastrointestinal endoscopy examination, a diagnosis of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), non-GC type, was made. F18-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed abnormal accumulations solely in the gastric wall (SUVmax = 14.5), the left adrenal gland (SUVmax = 14.3), and the right adrenal gland (SUVmax = 8.5). The clinical stage (Ann Arbor) was IVA, the serum LDH level was within the reference range, and the International Prognostic Index (IPI) was low-intermediate. The serum soluble IL-2 receptor level was within the reference range, and there was no evidence of HIV, EB virus, or autoimmune disease. After the completion of 4 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and 2 parallel cycles of prophylactic intrathecal (I.T.), an upper gastrointestinal endoscopy and a FDG-PET/CT examination showed complete remission (CR). The patient received 8 cycles of ritsuximab therapy, 6 cycles of CHOP, and 3 cycles of I.T. The patient has maintained a CR for about 14 months. A literature search revealed that malignant lymphoma with involvement confined to the adrenal gland and gastrointestinal tract is exceedingly rare, and only 3 cases of malignant lymphoma have been reported, with involvement of the stomach in 2 cases and the duodenum in 1 case. All of the cases were diagnosed as DLBCL. The case described herein represents the third case with involvement of the stomach.

  2. Predictive value of F-18 FDG PET/CT quantization parameters in diffuse large B cell lymphoma: a meta-analysis with 702 participants.

    PubMed

    Xie, Mixue; Wu, Kefei; Liu, Yan; Jiang, Qi; Xie, Yanhui

    2015-01-01

    F-18 fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) is considered to be the most beneficial imaging method for staging patients with lymphoma. Whether maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) acquired from F-18 FDG PET/CT are predictors of prognosis of diffuse large B cell lymphoma (DLBCL) is controversial, with some studies concluding that it is and others concluding the opposite. Therefore, a systematic review was performed to explore the relationship of F-18 FDG PET/CT quantization parameters with the prognosis of DLBCL. Seven trials with a total of 703 DLBCL patients were included for analysis. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS), and odds ratios (ORs) for 3-year PFS and OS were pooled using the STATA package. Combined results suggested a strong link between the high SUVmax, MTV and TLG values and the poor 3-year PFS with ORs of 2.59, 3.69 and 2.29, respectively. Similarly, high MTV and TLG values unfavorably influenced the 3-year OS with ORs of 5.40 and 2.19, respectively. The pooled results also showed that high SUVmax and MTV were negative predictors of PFS with HRs of 1.61 (p = 0.038) and 2.18 (p = 0.000), respectively. The TLG value was not predictive of PFS. And for OS, only high MTV was a strong predictor of poor prognosis in DLBCL with HR 2.99 (p = 0.000). Our results suggested that SUVmax and MTV may be significant prognostic markers for PFS and MTV may be the only predictor for OS in DLBCL.

  3. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma

    PubMed Central

    Goebeler, Marie-Elisabeth; Hess, Georg; Neumann, Svenja; Pfreundschuh, Michael; Adrian, Nicole; Zettl, Florian; Libicher, Martin; Sayehli, Cyrus; Stieglmaier, Julia; Zhang, Alicia; Nagorsen, Dirk; Bargou, Ralf C.

    2016-01-01

    Few patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) achieve prolonged disease-free survival. Blinatumomab, a bispecific T-cell engaging antibody construct, transiently links CD3-positive T cells to CD19-positive B cells. This phase 2 study evaluated stepwise (9-28-112 μg/d with weekly dose increases; n = 23) or flat (112 μg/d; n = 2) dosing of blinatumomab by continuous infusion, with dexamethasone prophylaxis, in patients with relapsed/refractory DLBCL. Patients received a median of 3 prior lines of therapy. Median time since last regimen was 1.5 months. Seventeen patients ended treatment in cycle 1 (induction), 7 in cycle 2 (consolidation), and 1 in retreatment. Among 21 evaluable patients, the overall response rate after 1 blinatumomab cycle was 43%, including complete responses (CRs) in 19%. Three patients had late CR in follow-up without other treatment. The most common adverse events with stepwise dosing were tremor (48%), pyrexia (44%), fatigue (26%), and edema (26%). Grade 3 neurologic events with stepwise dosing were encephalopathy and aphasia (each 9%) and tremor, speech disorder, dizziness, somnolence, and disorientation (each 4%). Of 5 (22%) patients who discontinued stepwise dosing because of adverse events, 4 (17%) had neurologic events. Most neurologic events resolved. The flat-dose cohort was stopped because of grade 3 neurologic events in both patients. Blinatumomab monotherapy appears effective in patients with relapsed/refractory DLBCL, a heavily pretreated patient population with a high unmet medical need. Further studies need to define the optimal approach to achieve the target dose without early dropout. The study was registered at www.clinicaltrials.gov as #NCT01741792. PMID:26755709

  4. Expression IRF/MUM1>25% Predictor to Three-year Survival of Diffuse Large B Cell Lymphoma in the Immunochemotherapy Era

    PubMed Central

    Sofo-Hafizovic, Alma; Chikha, Adisa; Gojak, Refet; Hadzimesic, Emina Suljovic

    2016-01-01

    Introduction: Non Hodgkin lymphoma-Diffuse large B cell lymphoma (DLBC) is composed of more varieties of one disease. Analysis and understanding of a wide range of characteristics of the disease, which include: clinical, immunohistochemical, cytogenetic and molecular characteristics may improve treatment results. Aim: achieving the estimated three-year survival and influence of IRF/MUM1 expression to three-year survival. Material and methods: A study was retrospective–prospective, patients were followed for seven years a period of dine. The study included 60 patients de novo DLBCL. Age was 18-72 years old, the average age 45 years, male 31 (51,7%) and female 29 (48.3%). Median follow-up was 47 months (3-91 months). To determine differentiation immunophenotype antibodies those were used anti-CD20, anti-CD10, anti-Bcl-6, IRF-4/MUM1, CD 138. Results: Included the GCB type was 65%. Impact prognostic index IPI>2 GBC vs non GBC p=0,038 X2. Statistically significant difference was confirmed compared to the IPI> 2 to 3 year OS p<0,0005 X2. Significantly longer three-year survival was provided in the group GCB 36 (92,3%) vs. non GCB 8 (38,1%) p=0,003 X2. Clinical and immunohistochemical factors showed a significant impact to three-year survival by univariate: LDH p=0,005, MUM1 p=0,003, while CD10 p=0,069 was confirmed on the level of borderline impact. Using multivariate analysis, expression MUM1 has the greatest impact p<0.0005 OR=0.083 (95% CI 0.23-0.303) on the disease outcome – three-year survival. Conclusion: expression MUM1 >25% has the greatest impact on the disease outcome – three-year survival. PMID:27994293

  5. Differential expression of viral agents in lymphoma tissues of patients with ABC diffuse large B-cell lymphoma from high and low endemic infectious disease regions

    PubMed Central

    Högfeldt, Therese; Jaing, Crystal; Loughlin, Kevin Mc; Thissen, James; Gardner, Shea; Bahnassy, Abeer A.; Gharizadeh, Baback; Lundahl, Joachim; Österborg, Anders; Porwit, Anna; Zekri, Abdel-Rahman N.; Khaled, Hussein M.; Mellstedt, Håkan; Moshfegh, Ali

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin's lymphoma (NHL) in adults, accounts for approximately 30–40% of newly diagnosed lymphomas worldwide. Environmental factors, such as viruses and bacteria, may contribute to cancer development through chronic inflammation and the integration of oncogenes, and have previously been indicated in cervical cancer, hepatocellular carcinoma, gastric cancer and lymphoproliferative disorders. In the present study, the presence of microbial agents was analyzed in the lymphoma tissue of patients with activated B-cell like (ABC) DLBCL. The present study compared two groups of patients from geographically varied regions that possess a difference in the prevalence of viral and other microbial agents. The patient populations were from Sweden (a low endemic infectious disease region) and Egypt (a high endemic infectious disease region). A differential expression of several viruses in lymphoma tissues was noted when comparing Swedish and Egyptian patients. JC polyomavirus (JCV) was detected in Swedish and Egyptian patients and, uniquely, the complete hepatitis B virus (HBV) genome was detected only in Egyptian lymphoma patients. None of these viruses were detected in control lymph tissues from Sweden or Egypt. In total, 38% of the Egyptian patients were found to have HBV surface antigens (HBsAgs) in their serum; however, HBsAgs were not found in any of the Swedish patients. The percentage of serum HBsAgs in Egyptian patients with ABC DLBCL was significantly increased compared with the general Egyptian population (P<0.05). The present study may support a notion that viral agents, including JCV and HBV, may be involved in the tumorigenesis of DLBCL in regions of high infectious disease. PMID:27698858

  6. Upfront consolidation combining yttrium-90 ibritumomab tiuxetan and high-dose therapy with stem cell transplantation in poor-risk patients with diffuse large B cell lymphoma.

    PubMed

    Fruchart, Christophe; Tilly, Hervé; Morschhauser, Franck; Ghesquières, Hervé; Bouteloup, Marie; Fermé, Christophe; Van Den Neste, Eric; Bordessoule, Dominique; Bouabdallah, Reda; Delmer, Alain; Casasnovas, René Olivier; Ysebaert, Loïc; Ciappuccini, Renaud; Briere, Josette; Gisselbrecht, Christian

    2014-12-01

    We evaluated the safety and efficacy of standard-dose yttrium-90 (Y(90)) ibritumomab tiuxetan combined with high-dose BEAM (carmustine, etoposide, cytarabine, and melphalan) after first-line induction treatment in young patients with poor prognoses diffuse large B cell lymphoma (DLBCL) (clinicaltrials.gov: NCT00689169). Seventy-five high-risk (≥2 International Prognostic Index [IPI] factors) consecutive DLBCL patients (≤65 years old) in complete remission (CR) or partial remission (PR) after rituximab chemotherapy were treated with Y(90) ibritumomab tiuxetan and BEAM regimen followed by autologous stem cell transplantation (ASCT). The median follow-up was 34 months. Of the 75 patients, 71 underwent ASCT and were eligible for analysis. Median time to reach a neutrophil count of >500/μL and platelet count of >20,000/μL was 11 days. Mucositis ≥3 (51%) occurred in most patients. Other adverse events were similar to those seen with BEAM alone. The overall response rate was 86%; 59 patients (83%) achieved a CR or unconfirmed CR. The 2-year event-free survival (EFS), overall survival (OS), and disease-free survival were 79%, 83%, and 91%, respectively. Disease status (CR/PR) and positron emission tomography (PET) findings before transplantation did not predict treatment failure. The IPI (2 versus >2) and maximum tumor diameter of ≥10 cm at diagnosis appeared to be prognosis factors for OS but not for EFS. Adding Y(90) ibritumomab tiuxetan to BEAM is safe and does not increase transplantation-related toxicity. First-line consolidation with Y(90) ibritumomab tiuxetan and high-dose chemotherapy induced high rates of EFS and OS in poor-prognosis patients with DLBCL, regardless of PET status after induction treatment and warrants a randomized study.

  7. Risk-tailored CNS prophylaxis in a mono-institutional series of 200 patients with diffuse large B-cell lymphoma treated in the rituximab era.

    PubMed

    Ferreri, Andrés J M; Bruno-Ventre, Marta; Donadoni, Giovanni; Ponzoni, Maurilio; Citterio, Giovanni; Foppoli, Marco; Vignati, Alessandro; Scarfò, Lydia; Sassone, Marianna; Govi, Silvia; Caligaris-Cappio, Federico

    2015-03-01

    The most effective strategy to prevent central nervous system (CNS) dissemination in diffuse large B-cell lymphoma (DLBCL) remains an important, unmet clinical need. Herein, we report a retrospective analysis of risk-tailored CNS prophylaxis in 200 human immunodeficiency virus-negative adults with DLBCL treated with rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or similar. High risk of CNS relapse was defined by involvement of specific extranodal organs, or simultaneous presence of advanced stage and high serum lactate dehydrogenase level; CNS prophylaxis with high-dose methotrexate ± intrathecal chemotherapy (IT) was routinely used in high-risk patients diagnosed after 2007. CNS relapse risk was low in 93 patients and high in 107; 40 high-risk patients received prophylaxis, which consisted of IT alone in 7. At a median follow-up of 60 months, one low-risk and nine high-risk patients (1% vs. 8%; P = 0·01) experienced CNS relapse. In the high-risk group, CNS relapses occurred in 8/67 (12%) patients who did not receive prophylaxis and in 1/40 (2·5%) patients who did; the latter occurred in a patient managed with IT alone. CNS relapse rate was 12% (9/74) for patients treated with "inadequate" prophylaxis (none or IT only) and 0% (0/33) for patients managed with intravenous prophylaxis (P = 0·03). In conclusion, high-dose methotrexate-based prophylaxis significantly reduces CNS failures in high-risk patients stratified by involvement of specific extranodal sites and International Prognostic Index.

  8. CARMA1- and MyD88-dependent activation of Jun/ATF-type AP-1 complexes is a hallmark of ABC diffuse large B-cell lymphomas.

    PubMed

    Juilland, Mélanie; Gonzalez, Montserrat; Erdmann, Tabea; Banz, Yara; Jevnikar, Zala; Hailfinger, Stephan; Tzankov, Alexandar; Grau, Michael; Lenz, Georg; Novak, Urban; Thome, Margot

    2016-04-07

    A hallmark of the diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) type, a molecular subtype characterized by adverse outcome, is constitutive activation of the transcription factor nuclear factor-κB (NF-κB), which controls expression of genes promoting cellular survival and proliferation. Much less, however, is known about the role of the transcription factor activator protein-1 (AP-1) in ABC DLBCL. Here, we show that AP-1, like NF-κB, was controlled by constitutive activation of the B-cell receptor signaling component caspase recruitment domain-containing membrane-associated guanylate kinase 1 (CARMA1) and/or the Toll-like receptor signaling component myeloid differentiation primary response gene 88 (MyD88) in ABC DLBCL cell lines. In contrast to germinal center (GC) B-cell (GCB) DLBCL, ABC DLBCL cell lines expressed high levels of the AP-1 family members c-Jun, JunB, and JunD, which formed heterodimeric complexes with the AP-1 family members activating transcription factor (ATF) 2, ATF3, and ATF7. Inhibition of these complexes by a dominant-negative approach led to impaired growth of a majority of ABC DLBCL cell lines. Individual silencing of c-Jun, ATF2, or ATF3 decreased cellular survival and revealed c-Jun/ATF2-dependent control of ATF3 expression. As a consequence, ATF3 expression was much higher in ABC vs GCB DLBCL cell lines. Samples derived from DLBCL patients showed a clear trend toward high and nuclear ATF3 expression in nodal DLBCL of the non-GC or ABC subtype. These findings identify the activation of AP-1 complexes of the Jun/ATF-type as an important element controlling the growth of ABC DLBCL.

  9. Epstein-Barr virus (EBV) positive diffuse large B cell lymphoma of the elderly-experience of a single center from Turkey.

    PubMed

    Ozsan, Nazan; Cagirgan, Seckin; Saydam, Guray; Gunes, Ajda; Hekimgil, Mine

    2013-08-01

    In the 2008 WHO lymphoma classification, 'EBV-positive diffuse large B cell lymphoma (DLBCL) of the elderly is included as a new provisional entity. We aimed to evaluate the morphological, immunophenotypic, and clinical characteristics of the cases diagnosed as 'EBV-positive DLBCL of the elderly' in our center and compared them with the 'EBV-negative DLBCL' patients older than 50 years of age. EBV status was detected by Epstein-Barr early RNA (EBER) in situ hybridization analysis. By immunohistochemistry, a panel of antibodies for CD10, Bcl-2, Bcl-6, IRF4/MUM1, CD30, and Ki67 was performed. Out of 149 DLBCL patients older than 50 years, without any known history of immunodeficiency or prior lymphoma, eight patients who fulfill the criteria were re-evaluated. Five patients were male and three were female, with a median age of 67.6 years. Four patients presented with nodal involvement; others presented with bone and soft tissue, bone marrow, and spleen infiltrations. Five cases revealed predominantly monomorphic morphology, one also contained focal areas consistent with polymorphous subtype; and three patients revealed a polymorphous infiltrate. When classified according to 'Hans criteria', five were non-GCB, and three were of the GCB cell phenotype. All cases with polymorphous morphology were revealed to be of the non-GCB cell phenotype, and all expressed IRF4/MUM1. Two patients died with disease, four patients are alive and in complete remission following R-CHOP therapy, and two patients have just recently been diagnosed. When compared with the EBV-negative group, there are no reliable morphological and immunohistochemical features indicating EBV positivity. Therefore, EBER in situ hybridization analysis is necessary to identify 'EBV-positive DLBCL of the elderly'. Further studies are needed to fully understand the details of this disease, which can lead to new treatment modalities.

  10. Development of EBV-encoded small RNA targeted PCR to classify EBV positive diffuse large B-cell lymphoma (DLBCL) of the elderly.

    PubMed

    Lee, Jaewang; Park, Min; Lee, Min Ho; Woo, Hyun Jun; Kim, Hyun-Woo; Yang, Ji Yeong; Eom, Yong-Bin; Kim, Sa-Hyun; Yoo, Changyoung; Kim, Jong-Bae

    2015-01-01

    Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly has been included in the 2008 WHO classification of lymphoma as a new provisional entity. EBV-positive DLBCL of the elderly is newly classified due to the main occurrence usually in patients of older than 50-year-old. This study was performed in 91 DLBCL patients from January 2002 to December 2012 in Catholic university of St. Vincent Hospital. Age distribution of the patients was 14~87-year-old. Specimens were collected from lymph nodes (n = 45) and extra-lymph nodes (n = 46). EBV encoded small RNA1 in situ hybridization (EBER1-ISH) known as a standard method for the diagnosis of DLBCL. In this study, nested PCR of DNA polymerase gene and EBER PCR were conducted to detect EBV. Presence of EBV was indicated in 3 samples (3.30%) by EBER-ISH, 26 samples (28.57%) by nPCR, and 3 samples (3.30%) by EBER PCR. The concordant results were obtained from EBER1-ISH and EBER PCR. Two samples were classified as EBV-positive DLBCL of the elderly among 91 DLBCL patients. Previously, the incidence rate of DLBCL of the elderly in Asia has been reported as 5~11%, but the result in this study showed a slightly lower incidence rate. To our knowledge, this is the first report on EBV-positive DLBCL of the elderly in Suwon area, Korea. EBER1-ISH and EBER PCR developed in this study may be helpful in classification of EBV-positive DLBCL of the elderly in future.

  11. QuantiGene Plex Represents a Promising Diagnostic Tool for Cell-of-Origin Subtyping of Diffuse Large B-Cell Lymphoma.

    PubMed

    Hall, John S; Usher, Suzanne; Byers, Richard J; Higgins, Rebekah C; Memon, Danish; Radford, John A; Linton, Kim M

    2015-07-01

    Emerging therapies targeting the molecularly distinct GCB and non-GCB/ABC subtypes of diffuse large B-cell lymphoma (DLBCL) have created the need to develop an accurate subtyping assay for routine use. We investigated the potential of QuantiGene Plex (QGP)-branched DNA signal amplification assay-for DLBCL subtyping. We performed in silico analysis of public DLBCL datasets to develop and validate a naïve Bayes classifier, and migrated the resulting 21-gene classifier to QGP and real-time quantitative PCR (qPCR) assays. Forty DLBCL formalin-fixed, paraffin-embedded tumors of known subtype (20 per subtype by gene expression profiling of paired fresh-frozen tissues) were reclassified, and results for QGP (on 38/40 for 21/21 targets) and qPCR (on 40/40 samples for 19/21 targets) compared for recapitulation of microarray data and classification accuracy. The 21-gene bayesian classifier achieved mean area under the curve values >0.9 on independent validation. QGP showed a higher correlation with microarray data (mean R(2) = 0.66 ± 0.05 versus 0.34 ± 0.07; P < 0.0001) and classification accuracy (92.1% versus 78.9%). The proportion of validated targets was also higher for QGP (85.7% versus 47.4%). The QGP protocol was rapid and simple to perform, at a cost similar to qPCR. These promising preliminary results strongly support ongoing work to develop a QGP companion diagnostic assay for DLBCL subtyping.

  12. Circulating microRNA-125b and microRNA-130a expression profiles predict chemoresistance to R-CHOP in diffuse large B-cell lymphoma patients

    PubMed Central

    YUAN, WANG XIN; GUI, YANG XI; NA, WANG NA; CHAO, JIANG; YANG, XIGUI

    2016-01-01

    Numerous studies have reported the aberrant expression profiles of microRNAs (miRNAs) in diffuse large B-cell lymphoma (DLBCL), although very few of these studies were concerned with chemoresistance to R-CHOP in DLBCL patients. This study was designed to assess the correlation between circulating miRNA expression and chemoresistance and prognosis in DLBCL patients. At the start of the study, we demonstrated that miRNA expression levels in serum were significantly associated with those in formalin-fixed, paraffin-embedded tissues, which indicated that circulating miRNAs may be powerful, non-invasive biomarkers reflecting miRNAs levels isolated from tumor tissue. Then from eight potential drug-resistant miRNAs which were deregulated in DLBCL and which had been reported to be associated with drug resistance in other carcinomas, we screened out the circulating miR-125b and miR-130a, which may related to R-CHOP resistance. Dynamic monitoring of the levels of circulating miR-125b and miR-130a further demonstrated that they were involved in recurrence, progression and chemoresistance in DLBCL patients. Finally, we demonstrated that high miR-125b indicated poor prognosis, as patients with higher miR-125b levels had a shorter overall survival. To our knowledge, this is the first study demonstrating that miR-125b and miR-130a are associated with the risk of chemoresistance in DLBCL patients, and that dynamic monitoring of the levels of circulating miR-125b and miR-130a predicts the therapeutic response and disease status of DLBCL patients. PMID:26870228

  13. Predictors of Local Recurrence After Rituximab-Based Chemotherapy Alone in Stage III and IV Diffuse Large B-Cell Lymphoma: Guiding Decisions for Consolidative Radiation

    SciTech Connect

    Jegadeesh, Naresh; Rajpara, Raj; Esiashvili, Natia; Shi, Zheng; Liu, Yuan; Okwan-Duodu, Derrick; Flowers, Christopher R.; Khan, Mohammad K.

    2015-05-01

    Purpose: The role of consolidative radiation therapy (RT) for stage III and IV diffuse large B-cell lymphoma (DLBCL) in the era of rituximab is not well defined. There is evidence that some patients with bulky disease may benefit, but patient selection criteria are not well established. We sought to identify a subset of patients who experienced a high local failure rate after receiving rituximab-based chemotherapy alone and hence may benefit from the addition of consolidative RT. Methods and Materials: Two hundred eleven patients with stage III and IV DLBCL treated between August 1999 and January 2012 were reviewed. Of these, 89 had a complete response to systemic therapy including rituximab and received no initial RT. Kaplan-Meier analysis and Cox proportional hazards regression were performed, with local recurrence (LR) as the primary outcome. Results: The median follow-up time was 43.9 months. Fifty percent of patients experienced LR at 5 years. In multivariate analysis, tumor ≥5 cm and stage III disease were associated with increased risk of LR. The 5-year LR-free survival was 47.4% for patients with ≥5-cm lesions versus 74.7% for patients with <5-cm lesions (P=.01). In patients with <5-cm tumors, the maximum standardized uptake value (SUVmax) was ≥15 in all patients with LR. The 5-year LR-free survival was 100% in SUV<15 versus 68.8% in SUV≥15 (P=.10). Conclusions: Advanced-stage DLBCL patients with stage III disease or with disease ≥5 cm appear to be at an increased risk for LR. Patients with <5-cm disease and SUVmax ≥15 may be at higher risk for LR. These patients may benefit from consolidative RT after chemoimmunotherapy.

  14. Impact of Consolidation Radiation Therapy in Stage III-IV Diffuse Large B-cell Lymphoma With Negative Post-Chemotherapy Radiologic Imaging

    SciTech Connect

    Dorth, Jennifer A.; Prosnitz, Leonard R.; Broadwater, Gloria; Diehl, Louis F.; Beaven, Anne W.; Coleman, R. Edward; Kelsey, Chris R.

    2012-11-01

    Purpose: While consolidation radiation therapy (i.e., RT administered after chemotherapy) is routine treatment for patients with early-stage diffuse large B-cell lymphoma (DLBCL), the role of consolidation RT in stage III-IV DLBCL is controversial. Methods and Materials: Cases of patients with stage III-IV DLBCL treated from 1991 to 2009 at Duke University, who achieved a complete response to chemotherapy were reviewed. Clinical outcomes were calculated using the Kaplan-Meier method and were compared between patients who did and did not receive RT, using the log-rank test. A multivariate analysis was performed using Cox proportional hazards model. Results: Seventy-nine patients were identified. Chemotherapy (median, 6 cycles) consisted of anti-CD20 antibody rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 65%); cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; 22%); or other (13%). Post-chemotherapy imaging consisted of positron emission tomography (PET)/computed tomography (CT) (73%); gallium with CT (14%); or CT only (13%). Consolidation RT (median, 25 Gy) was given to involved sites of disease in 38 (48%) patients. Receipt of consolidation RT was associated with improved in-field control (92% vs. 69%, respectively, p = 0.028) and event-free survival (85% vs. 65%, respectively, p = 0.014) but no difference in overall survival (85% vs. 78%, respectively, p = 0.15) when compared to patients who did not receive consolidation RT. On multivariate analysis, no RT was predictive of increased risk of in-field failure (hazard ratio [HR], 8.01, p = 0.014) and worse event-free survival (HR, 4.3, p = 0.014). Conclusions: Patients with stage III-IV DLBCL who achieve negative post-chemotherapy imaging have improved in-field control and event-free survival with low-dose consolidation RT.

  15. Additional Survival Benefit of Involved-Lesion Radiation Therapy After R-CHOP Chemotherapy in Limited Stage Diffuse Large B-Cell Lymphoma

    SciTech Connect

    Kwon, Jeanny; Kim, Il Han; Kim, Byoung Hyuck; Kim, Tae Min; Heo, Dae Seog

    2015-05-01

    Purpose: The purpose of this study was to evaluate the role of involved-lesion radiation therapy (ILRT) after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in limited stage diffuse large B-cell lymphoma (DLBCL) by comparing outcomes of R-CHOP therapy alone with R-CHOP followed by ILRT. Methods and Materials: We identified 198 patients treated with R-CHOP (median, 6 cycles) for pathologically confirmed DLBCL of limited stage from July 2004 to December 2012. Clinical characteristics of these patients were 33% with stage I and 66.7% with stage II; 79.8% were in the low or low-intermediate risk group; 13.6% had B symptoms; 29.8% had bulky tumors (≥7 cm); and 75.3% underwent ≥6 cycles of R-CHOP therapy. RT was given to 43 patients (21.7%) using ILRT technique, which included the prechemotherapy tumor volume with a median margin of 2 cm (median RT dose: 36 Gy). Results: After a median follow-up of 40 months, 3-year progression-free survival (PFS) and overall survival (OS) were 85.8% and 88.9%, respectively. Multivariate analysis showed ≥6 cycles of R-CHOP (PFS, P=.004; OS, P=.004) and ILRT (PFS, P=.021; OS, P=.014) were favorable prognosticators of PFS and OS. A bulky tumor (P=.027) and response to R-CHOP (P=.012) were also found to be independent factors of OS. In subgroup analysis, the effect of ILRT was prominent in patients with a bulky tumor (PFS, P=.014; OS, P=.030) or an elevated level of serum lactate dehydrogenase (LDH; PFS, P=.004; OS, P=.012). Conclusions: Our results suggest that ILRT after R-CHOP therapy improves PFS and OS in patients with limited stage DLBCL, especially in those with bulky disease or an elevated serum LDH level.

  16. A success story: how a single targeted-therapy molecule impacted on treatment and outcome of diffuse large B-cell lymphoma.

    PubMed

    Mian, Michael; Augustin, Florian; Kocher, Florian; Gunsilius, Eberhard; Willenbacher, Wolfgang; Zabernigg, August; Zangerl, Günther; Oexle, Horst; Schreieck, Stefan; Schnallinger, Michael; Fiegl, Michael

    2014-05-01

    Diffuse large B-cell lymphoma (DLBCL) is a rather aggressive disease and the natural course of this lymphoma is very dismal. However, first the introduction of anthracycline-containing chemotherapy regimens and then the addition of rituximab were important steps forward. Since no complete real-life analyses have yet been published, we analyzed all patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in the whole region of Tyrol and compared the results to a historical CHOP(-like)-treated cohort. Two hundred and nineteen consecutive patients underwent R-CHOP and 72% achieved a complete remission (CR); 20% suffered a relapse and 31% died. 5-Year progression-free survival (PFS) and overall survival (OS) were 56% and 69%, respectively. We identified several parameters influencing PFS and OS significantly in univariate analysis, but only stage III/IV and hemoglobin <13 g/dl were independent prognosticators for PFS and age >60 years for OS. In comparison to the CHOP(-like)-treated group, the CR rate was similar, while the percentage of relapse was nearly twice in the historical cohort, namely 44%. This translated into a dramatically improved PFS and OS for the R-CHOP group. In conclusion, in a real-life setting R-CHOP results in high percentages of response and long-term remission. Moreover we showed that in the rituximab era, factors other than the single parameters of the international prognostic index significantly influence PFS and OS. Finally, we confirm the independent impact of rituximab on the outcome of an unselected population with DLBCL.

  17. Epstein-Barr Virus-Positive Diffuse Large B cell Lymphoma in the Experience of a Tertiary Medical Center in Poland.

    PubMed

    Ziarkiewicz, Mateusz; Wołosz, Dominika; Dzieciątkowski, Tomasz; Wilczek, Ewa; Dwilewicz-Trojaczek, Jadwiga; Jędrzejczak, Wiesław Wiktor; Gierej, Beata; Ziarkiewicz-Wróblewska, Bogna

    2016-04-01

    The role of Epstein-Barr virus (EBV) in the biology and clinical characteristics of diffuse large B cell lymphoma (DLBCL) is still poorly defined. A new provisional entity EBV-positive DLBCL of the elderly has been described in Asian population. Its incidence and prognosis remains unknown in middle European patients. Clinical data and tissue samples were collected from 74 Caucasian patients with DLBCL, aged between 23 and 86 years, treated at a single institution. Lymphoma morphology was reassessed, laboratory procedures included in situ hybridization specific for EBV-encoded small RNAs (EBER), immunohistochemical staining for latent membrane protein and serological testing for EBV-specific antibodies. EBER staining revealed 12.2 % of EBV-positive cases, whereas 9.5 % were diagnosed as EBV-positive DLBCL of the elderly. Serologic EBV markers did not correlate with the presence of EBV in tissue samples (P > 0.10). Elderly EBV-positive cases had lower BCL-6 (P = 0.038) and higher CD30 (P = 0.049) expression and were characterized by higher progression risk (median time-to-progression 12.5 months vs not reached; P = 0.029) and a trend towards worse overall survival (median overall survival 24.5 months vs not reached; P = 0.059). EBV-positive DLBCL of the elderly occurs relatively frequently in Polish population and may be associated with inferior prognosis in comparison with DLBCL, not otherwise specified.

  18. The different roles of molecular classification according to upfront autologous stem cell transplantation in advanced-stage diffuse large B cell lymphoma patients with elevated serum lactate dehydrogenase.

    PubMed

    Kim, Yu Ri; Kim, Soo-Jeong; Cheong, June-Won; Yang, Deok-Hwan; Lee, Hyewon; Eom, Hyeon-Seok; Sung, Yong Oh; Kim, Hyo Jung; Kang, Hye Jin; Lee, Won-Sik; Park, Yong; Yang, Woo-Ick; Min, Yoo Hong; Kim, Jin Seok

    2016-09-01

    The non-germinal center B cell (non-GCB) subtype of diffuse large B cell lymphoma (DLBCL) is more related to poor prognosis than the GCB subtype. To investigate the role of molecular classification according to upfront autologous hematopoietic stem cell transplantation (ASCT), we retrospectively evaluated 219 newly diagnosed high-risk DLBCL patients. Eighty-one patients were in the ASCT group, and 138 patients were in the non-ASCT group. The ASCT group yielded significantly better overall survival (OS) and progression-free survival (PFS) than the non-ASCT group (p = 0.038 and p = 0.007), and patients with the non-GCB subtype were more related to inferior PFS than those with the GCB subtype (p = 0.020). After performing age-matching by using propensity scores, upfront ASCT continued to show better OS and PFS than non-ASCT (p = 0.046 and p = 0.026). In the non-ASCT group, the non-GCB subtype showed worse OS and PFS than the GCB subtype (p = 0.039 and p = 0.007). Patients who achieved complete response showed differences in OS and PFS according to molecular subtype (p = 0.007 and p = 0.002). In the ASCT group, there were no significant differences in OS and PFS according to molecular classification (p = 0.277 and p = 0.892). In conclusion, non-GCB subtype DLBCL patients showed poor OS and PFS in the non-ASCT group while they did not show clinical significance in the ASCT group. This suggests the possibility that upfront ASCT may improve the poor prognosis of non-GCB subtype in high-risk DLBCL.

  19. FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas

    PubMed Central

    Brown, P J; Wong, K K; Felce, S L; Lyne, L; Spearman, H; Soilleux, E J; Pedersen, L M; Møller, M B; Green, T M; Gascoyne, D M; Banham, A H

    2016-01-01

    The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full-length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (P<0.05). FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. In R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL patients (n=150), reduced HLA-DRA (<90% frequency) expression correlated with inferior overall survival (P=0.0003) and progression-free survival (P=0.0012) and with non-GCB subtype stratified by the Hans, Choi or Visco–Young algorithms (all P<0.01). In non-GCB DLBCL cases with <90% HLA-DRA, there was an inverse correlation with the frequency (P=0.0456) and intensity (P=0.0349) of FOXP1 expression. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients. PMID:26500140

  20. Validation of the NCCN-IPI for diffuse large B-cell lymphoma (DLBCL): the addition of β2 -microglobulin yields a more accurate GELTAMO-IPI.

    PubMed

    Montalbán, Carlos; Díaz-López, Antonio; Dlouhy, Ivan; Rovira, Jordina; Lopez-Guillermo, Armando; Alonso, Sara; Martín, Alejandro; Sancho, Juan M; García, Olga; Sánchez, Jose M; Rodríguez, Mario; Novelli, Silvana; Salar, Antonio; Gutiérrez, Antonio; Rodríguez-Salazar, Maria J; Bastos, Mariana; Domínguez, Juan F; Fernández, Rubén; Gonzalez de Villambrosia, Sonia; Queizan, José A; Córdoba, Raul; de Oña, Raquel; López-Hernandez, Andrés; Freue, Julian M; Garrote, Heidys; López, Lourdes; Martin-Moreno, Ana M; Rodriguez, Jose; Abraira, Víctor; García, Juan F

    2017-03-01

    The study included 1848 diffuse large B-cell lymphoma (DLBCL)patients treated with chemotherapy/rituximab. The aims were to validate the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) and explore the effect of adding high Beta-2 microglobulin (β2M), primary extranodal presentation and intense treatment to the NCCN-IPI variables in order to develop an improved index. Comparing survival curves, NCCN-IPI discriminated better than IPI, separating four risk groups with 5-year overall survival rates of 93%, 83%, 67% and 49%, but failing to identify a true high-risk population. For the second aim the series was split into training and validation cohorts: in the former the multivariate model identified age, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, Stage III-IV, and β2M as independently significant, whereas the NCCN-IPI-selected extranodal sites, primary extranodal presentation and intense treatments were not. These results were confirmed in the validation cohort. The Grupo Español de Linfomas/Trasplante de Médula ósea (GELTAMO)-IPI developed here, with 7 points, significantly separated four risk groups (0, 1-3, 4 or ≥5 points) with 11%, 58%, 17% and 14% of patients, and 5-year overall survival rates of 93%, 79%, 66% and 39%, respectively. In the comparison GELTAMO IPI discriminated better than the NCCN-IPI. In conclusion, GELTAMO-IPI is more accurate than the NCCN-IPI and has statistical and practical advantages in that the better discrimination identifies an authentic high-risk group and is not influenced by primary extranodal presentation or treatments of different intensity.

  1. CARMA1- and MyD88-dependent activation of Jun/ATF-type AP-1 complexes is a hallmark of ABC diffuse large B-cell lymphomas

    PubMed Central

    Juilland, Mélanie; Gonzalez, Montserrat; Erdmann, Tabea; Banz, Yara; Jevnikar, Zala; Hailfinger, Stephan; Tzankov, Alexandar; Grau, Michael; Lenz, Georg; Novak, Urban

    2016-01-01

    A hallmark of the diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) type, a molecular subtype characterized by adverse outcome, is constitutive activation of the transcription factor nuclear factor–κB (NF-κB), which controls expression of genes promoting cellular survival and proliferation. Much less, however, is known about the role of the transcription factor activator protein-1 (AP-1) in ABC DLBCL. Here, we show that AP-1, like NF-κB, was controlled by constitutive activation of the B-cell receptor signaling component caspase recruitment domain-containing membrane-associated guanylate kinase 1 (CARMA1) and/or the Toll-like receptor signaling component myeloid differentiation primary response gene 88 (MyD88) in ABC DLBCL cell lines. In contrast to germinal center (GC) B-cell (GCB) DLBCL, ABC DLBCL cell lines expressed high levels of the AP-1 family members c-Jun, JunB, and JunD, which formed heterodimeric complexes with the AP-1 family members activating transcription factor (ATF) 2, ATF3, and ATF7. Inhibition of these complexes by a dominant-negative approach led to impaired growth of a majority of ABC DLBCL cell lines. Individual silencing of c-Jun, ATF2, or ATF3 decreased cellular survival and revealed c-Jun/ATF2-dependent control of ATF3 expression. As a consequence, ATF3 expression was much higher in ABC vs GCB DLBCL cell lines. Samples derived from DLBCL patients showed a clear trend toward high and nuclear ATF3 expression in nodal DLBCL of the non-GC or ABC subtype. These findings identify the activation of AP-1 complexes of the Jun/ATF-type as an important element controlling the growth of ABC DLBCL. PMID:26747248

  2. Array-Based Comparative Genomic Hybridization Analysis Reveals Chromosomal Copy Number Aberrations Associated with Clinical Outcome in Canine Diffuse Large B-Cell Lymphoma

    PubMed Central

    Bresolin, Silvia; Marconato, Laura; Comazzi, Stefano; Te Kronnie, Geertruy; Aresu, Luca

    2014-01-01

    Canine Diffuse Large B-cell Lymphoma (cDLBCL) is an aggressive cancer with variable clinical response. Despite recent attempts by gene expression profiling to identify the dog as a potential animal model for human DLBCL, this tumor remains biologically heterogeneous with no prognostic biomarkers to predict prognosis. The aim of this work was to identify copy number aberrations (CNAs) by high-resolution array comparative genomic hybridization (aCGH) in 12 dogs with newly diagnosed DLBCL. In a subset of these dogs, the genetic profiles at the end of therapy and at relapse were also assessed. In primary DLBCLs, 90 different genomic imbalances were counted, consisting of 46 gains and 44 losses. Two gains in chr13 were significantly correlated with clinical stage. In addition, specific regions of gains and losses were significantly associated to duration of remission. In primary DLBCLs, individual variability was found, however 14 recurrent CNAs (>30%) were identified. Losses involving IGK, IGL and IGH were always found, and gains along the length of chr13 and chr31 were often observed (>41%). In these segments, MYC, LDHB, HSF1, KIT and PDGFRα are annotated. At the end of therapy, dogs in remission showed four new CNAs, whereas three new CNAs were observed in dogs at relapse compared with the previous profiles. One ex novo CNA, involving TCR, was present in dogs in remission after therapy, possibly induced by the autologous vaccine. Overall, aCGH identified small CNAs associated with outcome, which, along with future expression studies, may reveal target genes relevant to cDLBCL. PMID:25372838

  3. Impact of high-dose chemotherapy followed by auto-SCT for positive interim [18F] FDG-PET diffuse large B-cell lymphoma patients.

    PubMed

    Roland, V; Bodet-Milin, C; Moreau, A; Gastinne, T; Mahé, B; Dubruille, V; Maisonneuve, H; Juge-Morineau, N; Moreau, P; Jardel, H; Planche, L; Mohty, M; Moreau, P; Harousseau, J-L; Kraeber-Bodéré, F; Le Gouill, S

    2011-03-01

    [(18)F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is increasingly used for response assessment in diffuse large B-cell lymphoma (DLBCL). A positive interim FDG-PET was shown to be associated with an unfavorable outcome in high-grade non-Hodgkin's lymphomas. For positive interim FDG-PET patients, the question of increasing the intensity of treatment using high-dose chemotherapy followed by auto-SCT (HDC-ASCT) remains unanswered. We retrospectively analyzed the prognostic value of FDG-PET in 42 DLBCL patients who were systematically evaluated at time of diagnosis, before and after HDC-ASCT. Of note, HDC-ASCT was part of the initial treatment strategy, while FDG-PET results did not influence the treatment approach. Results and outcome were analyzed according to FDG-PET results before and after HDC-ASCT. Patients were classified into three groups according to FDG-PET results before and after HDC-ASCT: those who were negative before and after (-/-; n=25), positive before and negative after (+/-; n=9) or positive before and after (+/+; n=8). The median follow-up was 34.5 (range, 19-74) months. The median EFS was significantly lower for the +/+ group (27.4 months) as compared with other groups (median not reached; P=0.0001). More importantly, there was no difference in term of EFS between the -/- group compared with the +/- group. These results suggest that HDC-ASCT can significantly improve the bad prognosis, otherwise indicated by a positive interim FDG-PET.

  4. Prognostic significance of metabolic tumor burden by positron emission tomography/computed tomography in patients with relapsed/refractory diffuse large B-cell lymphoma

    PubMed Central

    Tateishi, Ukihide; Tatsumi, Mitsuaki; Terauchi, Takashi; Ando, Kiyoshi; Niitsu, Nozomi; Kim, Won Seog; Suh, Cheolwon; Ogura, Michinori; Tobinai, Kensei

    2015-01-01

    The aim of the present study was to investigate the feasibility of measuring metabolic tumor burden using [F-18] fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with bendamustine–rituximab. Because the standardized uptake value is a critical parameter of tumor characterization, we carried out a phantom study of 18F-FDG PET/CT to ensure quality control for 28 machines in the 24 institutions (Japan, 17 institutions; Korea, 7 institutions) participating in our clinical study. Fifty-five patients with relapsed or refractory DLBCL were enrolled. The 18F-FDG PET/CT was acquired before treatment, after two cycles, and after the last treatment cycle. Treatment response was assessed after two cycles and after the last cycle using the Lugano classification. Using this classification, remission was complete in 15 patients (27%) and incomplete in 40 patients (73%) after two cycles of therapy, and remission was complete in 32 patients (58%) and incomplete in 23 patients (42%) after the last treatment cycle. The percentage change in all PET/CT parameters except for the area under the curve of the cumulative standardized uptake value–volume histogram was significantly greater in complete response patients than in non-complete response patients after two cycles and the last cycle. The Cox proportional hazard model and best subset selection method revealed that the percentage change of the sum of total lesion glycolysis after the last cycle (relative risk, 5.24; P = 0.003) was an independent predictor of progression-free survival. The percent change of sum of total lesion glycolysis, calculated from PET/CT, can be used to quantify the response to treatment and can predict progression-free survival after the last treatment cycle in patients with relapsed or refractory DLBCL treated with bendamustine–rituximab. PMID:25495273

  5. MicroRNA-21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B-cell lymphoma

    PubMed Central

    Kim, Pil-Jong; Kim, Young-Goo; Nam, Soo Jeong; Paik, Jin Ho; Kim, Tae Min; Heo, Dae Seog; Kim, Chul-Woo; Jeon, Yoon Kyung

    2015-01-01

    The prognostic implications of miR-21, miR-17-92 and miR-155 were evaluated in diffuse large B-cell lymphoma (DLBCL) patients, and novel mechanism by which miR-21 contributes to the oncogenesis of DLBCL by regulating FOXO1 and PI3K/AKT/mTOR pathway was investigated. The expressions of miR-21, miR-17-92 and miR-155 measured by quantitative reverse-transcription-PCR were significantly up-regulated in DLBCL tissues (n=200) compared to control tonsils (P=0.012, P=0.001 and P<0.0001). Overexpression of miR-21 and miR-17-92 was significantly associated with shorter progression-free survival (P=0.003 and P=0.014) and overall survival (P=0.004 and P=0.012). High miR-21 was an independent prognostic factor in DLBCL patients treated with rituximab-combined chemotherapy. MiR-21 level was inversely correlated with the levels of FOXO1 and PTEN in DLBCL cell lines. Reporter-gene assay showed that miR-21 directly targeted and suppressed the FOXO1 expression, and subsequently inhibited Bim transcription in DLBCL cells. MiR-21 also down-regulated PTEN expression and consequently activated the PI3K/AKT/mTOR pathway, which further decreased FOXO1 expression. Moreover, miR-21 inhibitor suppressed the expression and activity of MDR1, thereby sensitizing DLBCL cells to doxorubicin. These data demonstrated that miR-21 plays an important oncogenic role in DLBCL by modulating the PI3K/AKT/mTOR/FOXO1 pathway at multiple levels resulting in strong prognostic implication. Therefore, targeting miR-21 may have therapeutic relevance in DLBCL. PMID:25909227

  6. Early Failure of Frontline Rituximab-containing Chemoimmunotherapy in Diffuse Large B-Cell Lymphoma does not Predict Futility of Autologous Hematopoietic Cell Transplantation

    PubMed Central

    Hamadani, Mehdi; Hari, Parameswaran N.; Zhang, Ying; Carreras, Jeanette; Akpek, Görgün; Aljurf, Mahmoud D.; Ayala, Ernesto; Bachanova, Veronika; Chen, Andy I.; Chen, Yi-Bin; Costa, Luciano J.; Fenske, Timothy S.; Freytes, César O.; Ganguly, Siddhartha; Hertzberg, Mark S.; Holmberg, Leona A.; Inwards, David J.; Kamble, Rammurti T.; Kanfer, Edward J.; Lazarus, Hillard M.; Marks, David I.; Nishihori, Taiga; Olsson, Richard; Reddy, Nishitha M.; Rizzieri, David A.; Savani, Bipin N.; Solh, Melhem; Vose, Julie M.; Wirk, Baldeep; Maloney, David G.; Smith, Sonali M.; Montoto, Silvia; Saber, Wael

    2014-01-01

    The poor prognosis of diffuse large B-cell lymphoma (DLBCL) patients relapsing within 1-year of initial diagnosis after first-line rituximab-based chemoimmunotherapy has created controversy about the role of autologous transplantation (auto-HCT) in this setting. We compared auto-HCT outcomes of chemosensitive DLBCL patients between 2000 and 2011 in two cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1-year of initial diagnosis. The ERF cohort was compared with those relapsing >1-year after initial diagnosis (Late Rituximab Failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Non-relapse mortality (NRM), progression/relapse, progression-free survival (PFS) and overall survival (OS) of ERF vs. LRF cohorts at 3-years were 9% (95%CI 6–13) vs. 9% (95%CI 5–13), 47% (95%CI 41–52) vs. 39% (95%CI 33–46), 44% (95%CI 38–50) vs. 52% (95%CI 45–59) and 50% (95 CI 44–56) vs. 67% (95%CI 60–74), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk (RR) 1.31, p=0.34). ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR 2.08, p<0.001) and overall mortality (RR 3.75, p<0.001) within the first 9 months post auto-HCT. Beyond this period, PFS and OS were not significantly different between ERF and LRF cohorts. Auto-HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS 44%), and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse. PMID:25008330

  7. Individual attitudes and perceived social norms: Reports on HIV/AIDS-related stigma among service providers in China

    PubMed Central

    Li, Li; Liang, Li-Jung; Wu, Zunyou; Lin, Chunqing; Wen, Yi

    2009-01-01

    This study examined HIV/AIDS-related stigma among Chinese service providers by comparing their personal attitudes toward people living with HIV/AIDS with their perception of social norms related to people living with HIV/AIDS. We randomly selected three provincial hospitals, four city/prefecture hospitals, 10 county hospitals, 18 township health clinics, and 54 village clinics from Yunnan, China. Doctors and nurses were randomly sampled proportionally to the doctor-nurse ratio of each hospital or clinic. Lab technicians were over-sampled in order to include an adequate representation in the analysis. A total of 1,101 service providers participated in a voluntary, anonymous survey where demographic characteristics, individual attitude and perceived social norms toward people living with HIV/AIDS, discrimination intent at work, general prejudicial attitude and knowledge on HIV/AIDS were measured. A majority of the sample demonstrated a similarity between their personal views and what they thought most people in society believe. Multiple logistic regressions revealed that participants who were younger or reported personal contact with people living with HIV/AIDS were significantly more likely to report personal attitudes toward the population that were more liberal than their perceived social norms. Holding a more liberal personal attitude toward people living with HIV/AIDS than perceived social norms was significantly and negatively related to the level of discrimination intent at work, perceived discrimination at interpersonal level and the level of general prejudicial attitude toward people living with HIV/AIDS. Results underscored the importance of understanding social norms and personal attitudes in studying HIV-related stigma and called for the incorporation of existing human capital into future HIV stigma reduction programs. Cette étude a examiné le VIH/SIDA lié à stigmatisation parmi les agences chinoises fournissant des soins en comparant leurs attitudes

  8. Diffuse Optical Intracluster Light as a Measure of Stellar Tidal Stripping: The Cluster CL0024+17 at z ~ 0.4 Observed at the Large Binocular Telescope

    NASA Astrophysics Data System (ADS)

    Giallongo, E.; Menci, N.; Grazian, A.; Gallozzi, S.; Castellano, M.; Fiore, F.; Fontana, A.; Pentericci, L.; Boutsia, K.; Paris, D.; Speziali, R.; Testa, V.

    2014-01-01

    We have evaluated the diffuse intracluster light (ICL) in the central core of the galaxy cluster CL0024+17 at z ~ 0.4 observed with the prime focus camera (Large Binocular Camera) at the Large Binocular Telescope. The measure required an accurate removal of the galaxies' light within ~200 kpc from the center. The residual background intensity has then been integrated in circular apertures to derive the average ICL intensity profile. The latter shows an approximate exponential decline as expected from theoretical cold dark matter models where the ICL is due to the integrated contribution of light from stars that are tidally stripped from the halo of their host galaxies due to encounters with other galaxies in the cluster cold dark matter (CDM) potential. The radial profile of the ICL over the galaxies intensity ratio (ICL fraction) is increasing with decreasing radius, but near the cluster center it starts to bend and then decreases where the overlap of the halos of the brightest cluster galaxies becomes dominant. Theoretical expectations in a simplified CDM scenario show that the ICL fraction profile can be estimated from the stripped over galaxy stellar mass ratio in the cluster. It is possible to show that the latter quantity is almost independent of the properties of the individual host galaxies but mainly depends on the average cluster properties. The predicted ICL fraction profile is thus very sensitive to the assumed CDM profile, total mass, and concentration parameter of the cluster. Adopting values very similar to those derived from the most recent lensing analysis in CL0024+17, we find a good agreement with the observed ICL fraction profile. The galaxy counts in the cluster core have then been compared with that derived from composite cluster samples in larger volumes, up to the clusters virial radius. The galaxy counts in the CL0024+17 core appear flatter and the amount of bending with respect to the average cluster galaxy counts imply a loss of total

  9. Effect of media use on HIV/AIDS-related knowledge and condom use in sub-Saharan Africa: a cross-sectional study.

    PubMed

    Jung, Minsoo; Arya, Monisha; Viswanath, Kasisomayajula

    2013-01-01

    It is known that the level of HIV/AIDS-related knowledge and the degree of condom use varies by socioeconomic status (SES). However, there is limited research on the effect of mass media use on HIV/AIDS-related cognitive and behavioral outcomes in low-income countries and how it might influence the association between SES and HIV-related outcomes. We investigated the moderating effect of media use on the relationship between SES and HIV/AIDS-related knowledge and condom use in sub-Saharan Africa in terms of communication inequalities. Cross-sectional data from the Demographic Health Surveys from 13 sub-Saharan countries (2004-10) were pooled. Gender-stratified multivariable poisson regression of 151,209 women and 68,890 men were used to calculate adjusted relative ratios and 95% confidence intervals for the associations between SES, media use, HIV-related outcomes, and condom use. We found significant disparities in mass media use among people from different SES groups as well as among countries. Education and wealth are strongly and positively associated with awareness of HIV/AIDS and knowledge about transmission and prevention of HIV/AIDS and are significantly associated with condom use. These associations are attenuated when the use of various types of mass media is added to the models, with newspapers showing the strongest effect. The findings of this study suggest that media use has the potential to blunt the impact of socioeconomic status though not com