tbuckley/cabot-search huggingface dataset:
Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions
Authors: Valentin Goede, Kirsten Fischer, Raymonde Busch, Anja Engelke, Barbara Eichhorst, Clemens M. Wendtner, Tatiana Chagorova, Javier de la Serna, Marie-Sarah Dilhuydy, Thomas Illmer, Stephen Opat, Carolyn J. Owen, Olga Samoylova, Karl-Anton Kreuzer, Stephan Stilgenbauer, Hartmut Döhner, Anton W. Langerak, Matthias Ritgen, Michael Kneba, Elina Asikanius, Kathryn Humphrey, Michael Wenger, Michael Hallek
Journal: New England Journal of Medicine (2014)

The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions.We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. The primary end point was investigator-assessed progression-free survival.The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab-chlorambucil or rituximab-chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with obinutuzumab-chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P=0.002). Treatment with obinutuzumab-chlorambucil, as compared with rituximab-chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the risk of infection was not increased.Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01010061.).
Fluid biomarkers in Alzheimer’s disease – current concepts
Authors: Christoffer Rosén, Oskar Hansson, Kaj Blennow, Henrik Zetterberg
Journal: Molecular Neurodegeneration (2013)

The diagnostic guidelines of Alzheimer's disease (AD) have recently been updated to include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. The CSF biomarkers total tau (T-tau), hyperphosphorylated tau (P-tau) and the 42 amino acid isoform of amyloid β (Aβ42) reflect the core pathologic features of AD, which are neuronal loss, intracellular neurofibrillary tangles and extracellular senile plaques. Since the pathologic processes of AD start decades before the first symptoms, these biomarkers may provide means of early disease detection. The updated guidelines identify three different stages of AD: preclinical AD, mild cognitive impairment (MCI) due to AD and AD with dementia. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review results from blood biomarker studies. In summary, the core AD CSF biomarkers have high diagnostic accuracy both for AD with dementia and to predict incipient AD (MCI due to AD). Longitudinal studies on healthy elderly and recent cross-sectional studies on patients with dominantly inherited AD mutations have also found biomarker changes in cognitively normal at-risk individuals. This will be important if disease-modifying treatment becomes available, given that treatment will probably be most effective early in the disease. An important prerequisite for this is trustworthy analyses. Since measurements vary between studies and laboratories, standardization of analytical as well as pre-analytical procedures will be essential. This process is already initiated. Apart from filling diagnostic roles, biomarkers may also be utilized for prognosis, disease progression, development of new treatments, monitoring treatment effects and for increasing the knowledge about pathologic processes coupled to the disease. Hence, the search for new biomarkers continues. Several candidate biomarkers have been found in CSF, and although biomarkers in blood have been harder to find, some recent studies have presented encouraging results. But before drawing any major conclusions, these results need to be verified in independent studies.
Comparison of laparoscopic and mini incision open donor nephrectomy: single blind, randomised controlled clinical trial
Authors: Niels F M Kok, May Y Lind, Birgitta M E Hansson, Desiree Pilzecker, Ingrid R A M Mertens zur Borg, Ben C Knipscheer, Eric J Hazebroek, Ine M Dooper, Willem Weimar, Wim C J Hop, Eddy M M Adang, Gert Jan van der Wilt, Hendrik J Bonjer, Jordanus A van der Vliet, Jan N M IJzermans
Journal: BMJ (2006)

To determine the best approach for live donor nephrectomy to minimise discomfort to the donor and to provide good graft function.Single blind, randomised controlled trial.Two university medical centres, the Netherlands.100 living kidney donors.Participants were randomly assigned to either laparoscopic donor nephrectomy or to mini incision muscle splitting open donor nephrectomy.The primary outcome was physical fatigue using the multidimensional fatigue inventory 20 (MFI-20). Secondary outcomes were physical function using the SF-36, hospital stay after surgery, pain, operating times, recipient graft function, and graft survival.Conversions did not occur. Compared with mini incision open donor nephrectomy, laparoscopic donor nephrectomy resulted in longer skin to skin time (median 221 v 164 minutes, P < 0.001), longer warm ischaemia time (6 v 3 minutes, P < 0.001), less blood loss (100 v 240 ml, P < 0.001), and a similar number of complications (intraoperatively 12% v 6%, P = 0.49, postoperatively both 6%). After laparoscopic nephrectomy, donors required less morphine (16 v 25 mg, P = 0.005) and shorter hospital stay (3 v 4 days, P = 0.003). During one year's follow-up mean physical fatigue was less (difference - 1.3, 95% confidence interval - 2.4 to - 0.1) and physical function was better (difference 6.2, 2.0 to 10.3) after laparoscopic nephrectomy. Function of the graft and graft survival rate of the recipient at one year censored for death did not differ (100% after laparoscopic nephrectomy and 98% after open nephrectomy).Laparoscopic donor nephrectomy results in a better quality of life compared with mini incision open donor nephrectomy but equal safety and graft function.
Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract
Authors: Darren Ruane, Lucas Brane, Bernardo Sgarbi Reis, Cheolho Cheong, Jordan Poles, Yoonkyung Do, Hongfa Zhu, Klara Velinzon, Jae-Hoon Choi, Natalie Studt, Lloyd Mayer, Ed C. Lavelle, Ralph M. Steinman, Daniel Mucida, Saurabh Mehandru
Journal: The Journal of Experimental Medicine (2013)

Developing efficacious vaccines against enteric diseases is a global challenge that requires a better understanding of cellular recruitment dynamics at the mucosal surfaces. The current paradigm of T cell homing to the gastrointestinal (GI) tract involves the induction of α4β7 and CCR9 by Peyer’s patch and mesenteric lymph node (MLN) dendritic cells (DCs) in a retinoic acid–dependent manner. This paradigm, however, cannot be reconciled with reports of GI T cell responses after intranasal (i.n.) delivery of antigens that do not directly target the GI lymphoid tissue. To explore alternative pathways of cellular migration, we have investigated the ability of DCs from mucosal and nonmucosal tissues to recruit lymphocytes to the GI tract. Unexpectedly, we found that lung DCs, like CD103+ MLN DCs, up-regulate the gut-homing integrin α4β7 in vitro and in vivo, and induce T cell migration to the GI tract in vivo. Consistent with a role for this pathway in generating mucosal immune responses, lung DC targeting by i.n. immunization induced protective immunity against enteric challenge with a highly pathogenic strain of Salmonella. The present report demonstrates novel functional evidence of mucosal cross talk mediated by DCs, which has the potential to inform the design of novel vaccines against mucosal pathogens.
Targeted Coating With Antigenic Peptide Renders Tumor Cells Susceptible to CD8+ T Cell-mediated Killing
Authors: Tae Heung Kang, Barbara Ma, Connie Wang, T.-C. Wu, Chien-Fu Hung
Journal: Molecular Therapy (2012)

The potency of immunotherapies targeting endogenous tumor antigens is hindered by immune tolerance. We created a therapeutic agent comprised of a tumor-homing module fused to a functional domain capable of selectively rendering tumor cells sensitive to foreign antigen-specific CD8+ T cell-mediated immune attack, and thereby, circumventing concerns for immune tolerance. The tumor-homing module is comprised of a single-chain variable fragment (scFv) that specifically binds to mesothelin (Meso), which is commonly overexpressed in human cancers, including ovarian tumors. The functional domain is comprised of the Fc portion of IgG2a protein and foreign immunogenic CD8+ T cell epitope flanked by furin cleavage sites (R), which can be recognized and cleaved by furin that is highly expressed in the tumor microenvironment. We show that our therapeutic protein specifically loaded antigenic epitope onto the surface of mesothelin-expressing tumor cells, rendering tumors susceptible to antigen-specific cytotoxic CD8+ T lymphocytes (CTL)-mediated killing in vitro and in vivo. Our findings have important implications for bypassing immune tolerance to enhance cancer immunotherapy. The potency of immunotherapies targeting endogenous tumor antigens is hindered by immune tolerance. We created a therapeutic agent comprised of a tumor-homing module fused to a functional domain capable of selectively rendering tumor cells sensitive to foreign antigen-specific CD8+ T cell-mediated immune attack, and thereby, circumventing concerns for immune tolerance. The tumor-homing module is comprised of a single-chain variable fragment (scFv) that specifically binds to mesothelin (Meso), which is commonly overexpressed in human cancers, including ovarian tumors. The functional domain is comprised of the Fc portion of IgG2a protein and foreign immunogenic CD8+ T cell epitope flanked by furin cleavage sites (R), which can be recognized and cleaved by furin that is highly expressed in the tumor microenvironment. We show that our therapeutic protein specifically loaded antigenic epitope onto the surface of mesothelin-expressing tumor cells, rendering tumors susceptible to antigen-specific cytotoxic CD8+ T lymphocytes (CTL)-mediated killing in vitro and in vivo. Our findings have important implications for bypassing immune tolerance to enhance cancer immunotherapy.
Risk of Secondary Leukemia After a Solid Tumor in Childhood According to the Dose of Epipodophyllotoxins and Anthracyclines: A Case-Control Study by the Société Française d’Oncologie Pédiatrique
Authors: Marie-Cécile Le Deley, Thierry Leblanc, Akthar Shamsaldin, Marie-Anne Raquin, Brigitte Lacour, Danièle Sommelet, Agnès Chompret, Jean-Michel Cayuela, Chantal Bayle, Alain Bernheim, Florent de Vathaire, Gilles Vassal, Catherine Hill
Journal: Journal of Clinical Oncology (2003)

Purpose: To estimate the risk of secondary leukemia as a function of the dose of epipodophyllotoxins and anthracyclines. Methods: We conducted a case-control study of the risk of secondary leukemia or myelodysplasia after a solid tumor in childhood within the Société Française d’Oncologie Pédiatrique, including 61 patients with leukemia matched with 196 controls. The characteristics of the first cancer, the patient’s family history of cancer, and the treatment (type, cumulative dose of chemotherapy, schedule of etoposide administration, and radiation dose delivered to active bone marrow) were compared in the two groups. Results: Only two factors were found to increase the risk of leukemia in multivariate analysis, namely, the type of the first tumor, with an excess risk in patients with Hodgkin’s disease (relative risk 6.4; 95% confidence interval [CI], 1.6 to 24) or osteosarcoma (relative risk 5; 95% CI, 1.3 to 19), and exposure to epipodophyllotoxins and anthracyclines. The risk of leukemia increased regularly with the cumulative dose of etoposide. In summary, patients who received between 1.2 and 6 g/m 2 of epipodophyllotoxins or more than 170 mg/m 2 of anthracyclines had a seven-fold higher risk (95% CI, 2.6 to 19) compared with patients who received lower doses or none of these drugs. The risk of leukemia in patients who received more than 6 g/m 2 of epipodophyllotoxins was multiplied by 197 (95% CI, 19 to 2,058). The risk of leukemia was not increased by exposure to alkylating agents or radiotherapy. Conclusion: Both epipodophyllotoxins and anthracyclines increase the risk of secondary leukemia. The current challenge is to minimize the mutagenic effects of these drugs by diminishing cumulative doses without losing the therapeutic benefits.
Low cost measures could save lives of three million babies a year
Authors: Rebecca Coombes
Journal: BMJ (2005)

The lives of nearly three million of the four million newborn babies who die worldwide each year could be saved by low cost, low tech interventions, a series of articles published by the Lancet shows.

Ninety nine per cent of the four million deaths occur in poor countries, although almost all published research relates to the 1% in rich countries.

The first paper in the series of articles, all published in the 3 March issue (www.thelancet.com), looks at when, where, and why newborn babies are dying and finds …
Uteroglobin Represses Allergen-induced Inflammatory Response by Blocking PGD2 Receptor–mediated Functions
Authors: Asim K. Mandal, Zhongjian Zhang, Rabindranath Ray, Moonsuk S. Choi, Bhabadeb Chowdhury, Nagarajan Pattabiraman, Anil B. Mukherjee
Journal: The Journal of Experimental Medicine (2004)

Uteroglobin (UG) is an antiinflammatory protein secreted by the epithelial lining of all organs communicating with the external environment. We reported previously that UG-knockout mice manifest exaggerated inflammatory response to allergen, characterized by increased eotaxin and Th2 cytokine gene expression, and eosinophil infiltration in the lungs. In this study, we uncovered that the airway epithelia of these mice also express high levels of cyclooxygenase (COX)-2, a key enzyme for the production of proinflammatory lipid mediators, and the bronchoalveolar lavage fluid (BALF) contain elevated levels of prostaglandin D2. These effects are abrogated by recombinant UG treatment. Although it has been reported that prostaglandin D2 mediates allergic inflammation via its receptor, DP, neither the molecular mechanism(s) of DP signaling nor the mechanism by which UG suppresses DP-mediated inflammatory response are clearly understood. Here we report that DP signaling is mediated via p38 mitogen-activated protein kinase, p44/42 mitogen-activated protein kinase, and protein kinase C pathways in a cell type-specific manner leading to nuclear factor-kappaB activation stimulating COX-2 gene expression. Further, we found that recombinant UG blocks DP-mediated nuclear factor-kappaB activation and suppresses COX-2 gene expression. We propose that UG is an essential component of a novel innate homeostatic mechanism in the mammalian airways to repress allergen-induced inflammatory responses.
Cognitive Behavior Therapy Augmentation of Pharmacotherapy in Pediatric Obsessive-Compulsive Disorder
Authors: Martin E. Franklin, Jeffrey Sapyta, Jennifer B. Freeman, Muniya Khanna, Scott Compton, Daniel Almirall, Phoebe Moore, Molly Choate-Summers, Abbe Garcia, Aubrey L. Edson, Edna B. Foa, John S. March
Journal: JAMA (2011)

The extant literature on the treatment of pediatric obsessive-compulsive disorder (OCD) indicates that partial response to serotonin reuptake inhibitors (SRIs) is the norm and that augmentation with short-term OCD-specific cognitive behavior therapy (CBT) may provide additional benefit.To examine the effects of augmenting SRIs with CBT or a brief form of CBT, instructions in CBT delivered in the context of medication management.A 12-week randomized controlled trial conducted at 3 academic medical centers between 2004 and 2009, involving 124 pediatric outpatients between the ages of 7 and 17 years with OCD as a primary diagnosis and a Children's Yale-Brown Obsessive Compulsive Scale score of 16 or higher despite an adequate SRI trial.Participants were randomly assigned to 1 of 3 treatment strategies that included 7 sessions over 12 weeks: 42 in the medication management only, 42 in the medication management plus instructions in CBT, and 42 in the medication management plus CBT; the last included 14 concurrent CBT sessions.Whether patients responded positively to treatment by improving their baseline obsessive-compulsive scale score by 30% or more and demonstrating a change in their continuous scores over 12 weeks.The medication management plus CBT strategy was superior to the other 2 strategies on all outcome measures. In the primary intention-to-treat analysis, 68.6% (95% CI, 53.9%-83.3%) in the plus CBT group were considered responders, which was significantly better than the 34.0% (95% CI, 18.0%-50.0%) in the plus instructions in CBT group, and 30.0% (95% CI, 14.9%-45.1%) in the medication management only group. The results were similar in pairwise comparisons with the plus CBT strategy being superior to the other 2 strategies (P < .01 for both). The plus instructions in CBT strategy was not statistically superior to medication management only (P = .72). The number needed-to-treat analysis with the plus CBT vs medication management only in order to see 1 additional patient at week 12, on average, was estimated as 3; for the plus CBT vs the plus instructions in CBT strategy, the number needed to treat was also estimated as 3; for the plus instructions in CBT vs medication management only the number needed to treat was estimated as 25.Among patients aged 7 to 17 years with OCD and partial response to SRI use, the addition of CBT to medication management compared with medication management alone resulted in a significantly greater response rate, whereas augmentation of medication management with the addition of instructions in CBT did not.clinicaltrials.gov Identifier: NCT00074815.
Chemopreventive Effects of Gefitinib on Nonsmoking-Related Lung Tumorigenesis in Activating Epidermal Growth Factor Receptor Transgenic Mice
Authors: Kadoaki Ohashi, Nagio Takigawa, Masahiro Osawa, Eiki Ichihara, Hiromasa Takeda, Toshio Kubo, Seiki Hirano, Tadashi Yoshino, Minoru Takata, Mitsune Tanimoto, Katsuyuki Kiura
Journal: Cancer Research (2009)

Abstract Twenty-five percent of all lung cancer cases are not attributable to smoking. Epidermal growth factor receptor (EGFR) mutations, which are involved in ∼50% of nonsmoker lung cancer, are positively correlated with responsiveness to gefitinib, and inversely correlated with smoking history. Activating EGFR mutations play a critical role in the carcinogenesis of nonsmoking-related lung cancer. To investigate the chemopreventive effects of gefitinib on nonsmoking-related lung cancer, we generated transgenic mice expressing EGFR L858R in type II pneumocytes constitutively using the surfactant protein-C promoter. The transgenic mice invariably developed atypical adenomatous hyperplasia at age 4 weeks and multifocal adenocarcinoma of varying sizes at age 7 weeks. Notably, the expression levels of phosphorylated and total ErbB2, ErbB3, and thyroid transcription factor-1 were elevated in the transgenic mice compared with wild-type controls at age 3 weeks. Administration of gefitinib to 3-week-old transgenic mice for 1 week before carcinogenesis reduced the amount of phosphorylated EGFR in the lungs of the mice to the baseline level. Gefitinib (5 mg/kg/d; n = 5, 5, and 15) or vehicle (n = 5, 5, and 15) was administered to transgenic mice from age 3 to 8, 13, and 18 weeks, respectively. The numbers of lung tumors in the control and gefitinib-treated groups were 1.75, 5.8, 10.2, and 0 (P &amp;lt; 0.05), respectively. No fatal toxic events occurred in either group, and gefitinib inhibited tumorigenesis completely in this mouse model. These results suggest the utility of molecular targeted chemoprevention against nonsmoking-related lung cancer. [Cancer Res 2009;69(17):7088–95]
Clinical Benefit of Allogeneic Melanoma Cell Lysate–Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients
Authors: Han Chong Toh, Who-Whong Wang, Whay Kuang Chia, Pia Kvistborg, Li Sun, Kelly Teo, Yee Peng Phoon, Yatanar Soe, Sze Huey Tan, Siew Wan Hee, Kian Fong Foo, Simon Ong, Wen Hsin Koo, Mai-Britt Zocca, Mogens H. Claesson
Journal: Clinical Cancer Research (2009)

PURPOSE: We evaluated the clinical benefit of an allogeneic melanoma cell lysate (MCL)-pulsed autologous dendritic cell (DC) vaccine in advanced colorectal cancer patients expressing at least one of six MAGE-A antigens overexpressed by the cell line source of the lysate. EXPERIMENTAL DESIGN: DCs were cultured from peripheral blood mononuclear cells (PBMC), pulsed with the allogeneic MCL, and matured using cytokines that achieved high CD83- and CCR7-expressing DCs. Each patient received up to 10 intradermal vaccinations (3-5 x 10(6) cells per dose) at biweekly intervals. RESULTS: Twenty patients received a total of 161 vaccinations. Treatment was well tolerated and quality of life measurements did not vary much across time. One patient experienced partial response [5%; 95% confidence interval (CI), 1-24%] and seven achieved stable disease (35%; 95% CI, 18-57%), one of whom also achieved late tumor regression, yielding a clinical benefit response rate of 40% (95% CI, 22-61%). Although overall median progression-free survival was 2.4 months (95% CI, 1.9-4.1 months), five patients (25%) experienced prolonged progression-free survival (>6 months), two of whom (10%) remain progression-free for >27 and >37 months, respectively. This result is particularly meaningful as all patients had progressive disease before treatment. Overall, DC vaccination was associated with a serial decline in regulatory T cells. Using an antibody array, we characterized plasma protein profiles in responding patients that may correlate with vaccine activity and report a prevaccination protein signature distinguishing responders from nonresponders. CONCLUSION: This phase II vaccine study using mature, MCL-pulsed DCs has shown promising results and warrants further evaluation in a prospective randomized setting. (Clin Cancer Res 2009;15(24):7726-36).