tbuckley/cabot-search huggingface dataset:
Bortezomib, rituximab, and risk of graft-versus-host disease (GVHD) after BEAM conditioning for allogeneic stem cell transplantation (alloSCT).
Authors: Kamal Chamoun, Alison M Gulbis, Denai Milton, Elias Jabbour, Francesco Turturro, Issa F. Khouri
Journal: Journal of Clinical Oncology (2017)

e18543 Background: GVHD remains the main limitation of alloSCT and is exacerbated by the intensity of the conditioning regimen. In a recent study, the risk of acute grade II-IV GVHD and extensive chronic GVHD (cGVHD) after a nonmyelobaltive (NMA) regimen was 11%, and 26%, respectively (Khouri I. Blood 2014 124:2306). Higher rates were previously observed (32% and 54%, respectively) with the BEAM regimen. Based on clinical data showing a reduction in GVHD with the use of rituximab or bortezomib, we conducted a phase I/II study evaluating the addition of bortezomib to rituximab+BEAM in patients (pts.) who were not eligible for NMA alloSCT. Methods: Bortezomib was administered at 1.3 mg/m 2 IV on days -13, -6, -1 and +2. The dose was later reduced to 1 mg/m 2 after the occurrence of C. Difficile colitis in the first 3 pts. leading to 2 deaths. Rituximab was given on day -13 at a dose of 375 mg/m 2 , then at 1000 mg/m 2 on days -6, +1, and +8 of alloSCT. BEAM was administered between days -6 and -1. All pts. received our standard GVHD prophylaxis with tacrolimus and methotrexate. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving matched unrelated donor (MUD) or mismatched (MM) transplants. Results: Thirty-nine pts. were studied. Median age was 54 yrs. Thirteen (33%) and 26 (67%) pts. had indolent or aggressive lymphoma histologies, respectively. Sixteen (41%) pts. were refractory. Twenty-two (56%) received alloSCT from HLA-compatible siblings, 16 (41%) from MUDs and 1 (3%) from mm donors. Peripheral blood was the source of stem cells in 97% of pts. ABO and CMV-mismatch rates were 56% had 50%, respectively. Median follow up surviving patients was 65 mos. Five-year OS and PFS rates were 35% and 28%, respectively. The CI of acute grade II-IV, III-IV, and cGVHD were 55%, 34%, and 41%, respectively. No predictor for acute GVHD was identified. Instead, we found that sex-mismatched transplants were predictive of a higher risk of cGVHD ( P= 0.01). Conclusions: The current trial is the first one evaluating the safety and efficacy of bortezomib plus rituximab as a part of the BEAM regimen for alloSCT. A better prophylaxis regimen is needed to lessen the risk of GVHD in this setting. Clinical trial information: NCT00439556.
Erratum: The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption
Authors: R Spanagel, G Pendyala, C Abarca, T Zghoul, C Sanchis-Segura, M C Magnone, J Lascorz, M Depner, D Holzberg, M Soyka, S Schreiber, F Matsuda, M Lathrop, G Schumann, U Albrecht
Journal: Nature Medicine (2005)
Synovial Immunophenotype and Anti–Citrullinated Peptide Antibodies in Rheumatoid Arthritis Patients
Authors: Carl Orr, Aurelie Najm, Monika Biniecka, Trudy McGarry, Chin‐Teck Ng, Francis Young, Ursula Fearon, Douglas J. Veale
Journal: Arthritis & Rheumatology (2017)

Serum anti-citrullinated peptide antibodies (ACPAs) may be present before the development of rheumatoid arthritis (RA) and may be predictive of more severe, erosive disease. This study was undertaken to examine the synovial tissue immunophenotype according to ACPA status in patients with RA, as well as the response to treatment and erosion status.Consecutive RA patients were prospectively recruited and underwent clinical and serologic assessments before and after treatment. Radiologic assessment was performed at the time of clinical follow-up. Synovial tissue was immunostained for specific markers of B cells (CD19), T cells (CD3, CD4, and CD8), macrophages (CD68), and blood vessels (factor VIII). Serum CXCL13 levels were quantified by enzyme-linked immunosorbent assay. Synovial tissue sections were analyzed for immunophenotype according to ACPA status, using a validated semiquantitative scoring method, and also analyzed for the presence of lymphoid aggregates. Response to treatment with nonbiologic or biologic disease-modifying antirheumatic drugs was assessed using the European League Against Rheumatism (EULAR) response criteria.In total, 123 subjects (78 ACPA+) were included. Compared to ACPA- RA patients, synovium from ACPA+ RA patients was characterized by significantly higher levels of CD19+ B cells and CD3+ and CD8+ T cells (each P < 0.05), and CD19+ B cell levels were significantly higher in patients who were naive to treatment. The CD19+ B cell infiltrate level was higher in patients with erosions at follow-up (P = 0.0128). Levels of lymphoid aggregates of CD19+ B cells were significantly higher in ACPA+ patients (P < 0.05), and this was associated with increased serum CXCL13 levels. The EULAR response was significantly associated with the level of CD3+ T cell infiltrates (P < 0.05), while CD68+ macrophage and CD8+ T cell levels were predictive of the response to tumor necrosis factor inhibitors (P < 0.05).The results of this prospective study demonstrate that the levels of synovial B cell infiltrates and lymphoid aggregates were significantly higher in ACPA+ RA patients, especially those who were naive to treatment. In addition, ACPA+ subjects developed more erosions during progression of the disease and had higher serum levels of CXCL13. The EULAR response to therapy in ACPA+ RA patients was associated with increased levels of T cell and macrophage markers.
Cytokine release syndrome (CRS) and neurotoxicity (NT) after CD19-specific chimeric antigen receptor- (CAR-) modified T cells.
Authors: Cameron John Turtle, Kevin Anthony Hay, Juliane Gust, Laila-Aicha Hanafi, Daniel Li, W. Conrad Liles, Mark Wurfel, Susanna Harju-Baker, David Myerson, Luis Gonzalez-Cuyar, Cecilia CS Yeung, Stanley R. Riddell, David G. Maloney
Journal: Journal of Clinical Oncology (2017)

3020 Background: CD19 CAR-T cells have produced impressive responses in CD19 + ALL, NHL and CLL. Detailed understanding of the presentation and pathogenesis of CRS and NT will facilitate safe CAR-T cell use in multicenter trials. Methods: We treated 161 adults with B-ALL, NHL or CLL with anti-CD19 CAR-T cells, formulated in a 1:1 CD4/CD8 ratio and infused after lymphodepletion chemotherapy in a dose finding study (NCT 01865617) to identify a MTD in each disease. Results: 133 patients (pts) completed toxicity assessment. CRS developed in 71% (60% gr 1-2, 4% gr 3, 8% gr ≥4). Fever was the first sign of CRS and preceded organ toxicity, allowing safe outpatient administration of CAR-T cells. NT was observed in 40% (19% gr 1-2, 16% gr 3, 5% gr ≥4) and gr ≥3 NT presented a median of 4.5 days after CRS onset. The time from onset to peak of NT was 2 days. CRS and NT were reversible with the exception of 6 pts who died, 4 during the dose-finding phase of the study. In multivariable analyses, higher CAR-T cell dose and malignant B cells in marrow (BM) were associated with CRS; and CAR-T cell dose, malignant BM B cells, more intensive lymphodepletion, and prior neurologic comorbidities were associated with NT. Probability curves of response, CRS and NT in relation to blood CAR-T cell counts show that toxicity mitigation by CAR-T cell dose reduction may be feasible in B-ALL without impairing BM response; however, dose reduction may reduce nodal response in NHL and CLL. Analysis of clinical parameters revealed that pts who later developed severe CRS or NT could be identified early after CAR-T cell infusion by higher fever, greater vascular instability, and more severe hypoalbuminemia. Paired serum-CSF studies and autopsy data suggest blood-brain barrier disruption in severe NT. High serum IL-6, IL-15, MCP-1 and IL-10, and endothelial activation markers on day 1 after infusion correlated with subsequent toxicity, which identifies pts for early intervention to prevent severe toxicity. Conclusions: CAR-T cells can be safely administered in the outpatient setting. Clinical and laboratory biomarkers allow early identification of a small subset of pts who might develop serious toxicity, facilitating study of preventive strategies. Clinical trial information: NCT 01865617.
Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine
Authors: Lichen Jing, Jürgen Haas, Tiana M. Chong, Joseph J. Bruckner, Greg C. Dann, Lichun Dong, Joshua O. Marshak, Christopher L. McClurkan, Tori N. Yamamoto, Susanne M. Bailer, Kerry J. Laing, Anna Wald, Georges M.G.M. Verjans, David M. Koelle
Journal: Journal of Clinical Investigation (2012)

In Table 4, line 12, for HLA allele A*0201, ORF UL27, the range given for HSV-1 aa was incorrect.
Trilateral overlap of tuberculosis, diabetes and HIV-1 in a high-burden African setting: implications for TB control
Authors: Tolu Oni, Natacha Berkowitz, Mmamapudi Kubjane, Rene Goliath, Naomi S. Levitt, Robert J. Wilkinson
Journal: European Respiratory Journal (2017)

The diabetes mellitus burden is growing in countries where tuberculosis (TB) and HIV-1 remain major challenges, threatening TB control efforts. This study determined the association between TB and diabetes/impaired glucose regulation in the context of HIV-1. A cross-sectional study was conducted at a TB clinic in Cape Town (South Africa). Participants were screened for diabetes and impaired glucose regulation using fasting plasma glucose, oral glucose tolerance test and glycated haemoglobin (HbA1c). 414 TB and 438 non-TB participants were enrolled. In multivariable analysis, diabetes was associated with TB (OR 2.4, 95% CI 1.3–4.3; p=0.005), with 14% population-attributable risk fraction; however, this association varied by diagnostic test (driven by HbA1c). The association remained significant in HIV-1-infected individuals (OR 2.4, 95% CI 1.1–5.2; p=0.030). A high prevalence of impaired glucose regulation (65.2% among TB cases) and a significant association with TB (OR 2.3, 95% CI 1.6–3.3; p&lt;0.001) was also found. Diabetes and impaired glucose regulation prevalence was high and associated with TB, particularly in HIV-1-infected individuals, highlighting the importance of diabetes screening. The variation in findings by diagnostic test highlights the need for better glycaemia markers to inform screening in the context of TB and HIV-1.
Nephron-Sparing Surgery for Renal Cell Carcinoma
Authors: Andrew C. Novick
Journal: Annual Review of Medicine (2002)

▪ Abstract Nephron-sparing surgery (NSS) provides effective curative therapy for patients with localized renal cell carcinoma. In patients with imperative indications, it represents an alternative to renal replacement therapy. For selected patients with systemic comorbidities that threaten global renal function, NSS preserves unaffected nephrons with excellent cancer-specific survival. Elective partial nephrectomy for patients with a small (≤4 cm), unifocal tumor and a normal contralateral kidney is associated with a low risk (0%–3%) of local recurrence and cancer-specific survival rates of 90%–100%. Comparisons between radical and partial nephrectomy demonstrate equivalent cancer control over five years. Minimally invasive techniques of NSS are feasible but await improved technologies and long-term outcome data before they become fully acceptable treatment options.
Abstract P066: Imaging Autophagy in Living Mice
Authors: Roberta A Gottlieb, M R Sayen, Chengqun Huang, Jennifer Ramil, Bruce Ito, Robert M Mentzer
Journal: Circulation Research (2011)

Autophagy is a homeostatic response to cellular stress. It has been shown to be potently upregulated in the heart in response to a variety of interventions. However, to date, it has not been possible to monitor autophagy without sacrificing the animal. Here we report the use of the Caliper Life Sciences Spectrum In Vivo Imaging System (IVIS) to image autophagy in homozygous transgenic mice expressing mCherryLC3 under control of the alpha myosin heavy chain promoter. Autophagy was stimulated by the administration of rapamycin (2mg/kg), and autophagosomal flux was blocked by administration of chloroquine (10mg/kg) ip. Mice were imaged at baseline and four hours later, using a protocol of 3 acquisitions of 15 seconds each. Total flux was 3.19±0.72 before drug administration and 3.93+1.10 after 4 hr, p&lt;;0.01, n=14. These results show for the first time imaging of autophagy in hearts of live mice.
Patient Subgroup Analysis of Quality-of-Life Outcomes in Checkmate 205, a Phase 2 Study of Nivolumab in Patients with Classical Hodgkin Lymphoma
Authors: Andreas Engert, Fiona Taylor, Bryan Bennett, Ishan Hirji, Kim Cocks, Jeffrey McDonald, Erin Mann, Kazunobu Kato, David Cella
Journal: Blood (2016)
Abstract 10862: The Effects of a New Medication Monitoring Programme on Blood Pressure Control Among Elderly Home Residents With Multiple Medications
Authors: Martin CS Wong, Harry HX Wang, Mandy WM Kwan, Shannon TS Li, Sian M Griffiths
Journal: Circulation (2015)

Objective: A high prevalence of hypertension among the elderly has raised public concern in Asia particularly in Hong Kong. It is commonly observed among elderly being prescribed with more than one antihypertensive agent. However, poor adherence can serve as one of the major causes of suboptimal blood pressure (BP) control, and particular in elderly homes where the residents often lack family support. The study aimed to evaluate the effects of a new medication monitoring programme on BP control among elderly home residents with multiple medications. Methods: We recruited study subjects from three elderly homes enrolled in a pharmacist-led home-based medication monitoring programme launched by the Hong Kong Pharmaceutical Care Foundation. The programme aimed to optimise drug therapy and achieve better BP control. We used a cluster sampling to recruit elderly people (aged ≥65 years) prescribed with multiple medications, who were then followed up for six months. Subjects in the intervention group received medications under pharmacist-led medication monitoring programme, while the control group received usual care. Intention-to-treat analysis was adopted. Systolic BP and diastolic BP were measured at each 3-monthly follow-up as primary outcomes. Secondary outcomes included healthcare utilisation and staff satisfaction. Repeated measures analysis of variance (RMANOVA) was used to estimate the intervention effect after adjusting for other covariates. Results: A total of 290 residents were recruited. The study showed distinct patterns of changes in SBP and DBP between groups. After 6 months, participants in the intervention group (n=200) had an average of 5.16mmHg (p=0.134) and 2.66mmHg (p=0.198) decrease in SBP and DBP, respectively; while the control group (n=90) showed 12.40mmHg (p=0.027) and 6.60mmHg (p=0.061) increase in SBP and DBP, respectively, after adjusting for other covariates. Conclusions: Elderly home residents enrolled in this new pharmacist-led home-based medication monitoring programme had better BP parameters, suggesting that future programmes on other cardiovascular disease medications based on similar approach could potentially be effective in achieving favourable outcomes among the elderly population in primary care.
SP0056 Update of the T2T recommendations in spa
Authors: D Van Der Heijde
Journal: Annals of the Rheumatic Diseases (2017)

In 2013 the first recommendations for treating spondyloarthritis to target (T2T) were published. These followed the reasoning for the T2T recommendations for rheumatoid arthritis. Although the systematic literature review at that time did not provide evidence to support the recommendations, five overarching principles and 11 recommendations were formulated. There were 9 commen recommendations for axial SpA, peripheral SpA and psoriatic arthritis and 2 additional recommendations for each subgroup specifically. In 2017 the T2T working group met again to update the recommendations. This was based on an updated systematic literature review. Data had been published that there is indeed a clear link between inflammation and subsequent longterm outcomes, which is the basis for the T2T principles. SpA is characterised by musculoskeletal signs and symptoms (arthritis, enthesitis, dactylitis, axial disease) but also extra-articular manifestations (psoriasis, inflammatory bowel disease, anterior uveitis) are important manifestations. Moreover, comborbidities (such as osteoporosis, cardiovascular disease). All these manifestations are taken into account in the formulation of the recommendations. The overarching principles were kept largely identical. Some changes in the wording were made for a better understanding, but no fundamental changes were made. A total of 11 recommendations were formulated. These are now for all subgroups of SpA and no specific recommendations are proposed. In principle, the treatment target is remission or inactive disease of musculoskeletal and extra-articulaur manifestations, and the target should be individualised. It is important that remission/inactive disease should be based on a combination of clinical and laboratory parameters, and disease activity should be measured on the basis of clinical signs and symptoms as well as acute phase reactants. This is important to realise, e.g. in axial SpA as patient reported outcomes only are at best weakly correlated with structural damage. In certain circumstances, low disease activity may be an alternative target. Because of the heterogeneous presentation of SpA, not only the target, but also the assessments should be individualised. Both in the overarching principles and in the recommendation the shared decision between patient and rheumatologist is listed as the basis of the T2T management. The updated recommendations will be presented. <h3>Disclosure of Interest</h3> D. Van Der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, UCB, Employee of: Imaging Rheumatology
Utilizing PET Imaging to Study Mitochondrial Respiration and Dynamics in Lung Cancer
Authors: M. Momcilovic, A. Jones, S. Bailey, C. Waldmann, J. Lee, L. Stiles, M. Cilluffo O.Shirihai, S.M. Dubinett, S. Sadeghi, D. Shackelford
Journal: Journal of Thoracic Oncology (2017)
Abstract 105: Cognitive Deficits at Discharge in Cardiac Arrest Survivors Treated With Therapeutic Hypothermia: Is "Good" as Good as We Think?
Authors: Mary Ann Peberdy, Michelle R Gossip, Charlotte S Roberts, Sharon Bednar, Michael C Kurz, Renee D Reid, Harinder Dhindsa, Joseph P Ornato
Journal: Circulation (2013)

Background: Cognitive deficits may be missed by CPC and Modified Rankin scoring done at discharge (DC) after cardiac arrest (CA). Cognitive dysfunction is common after brain injury and may lead to ...
Class II Eplet Mismatch Modulates Tacrolimus Trough Levels Required to Prevent Donor-Specific Antibody Development
Authors: Chris Wiebe, David N. Rush, Thomas E. Nevins, Patricia E. Birk, Tom Blydt-Hansen, Ian W. Gibson, Aviva Goldberg, Julie Ho, Martin Karpinski, Denise Pochinco, Atul Sharma, Leroy Storsley, Arthur J. Matas, Peter W. Nickerson
Journal: Journal of the American Society of Nephrology (2017)

Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II de novo donor-specific antibody (dnDSA) development correlates with tacrolimus trough levels and the recipient's individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before dnDSA development in the context of HLA-DR/DQ eplet mismatch. HLA-DR/DQ eplet mismatch was a significant multivariate predictor of dnDSA development. Recipients treated with a cyclosporin regimen had a 2.7-fold higher incidence of dnDSA development than recipients on a tacrolimus regimen. Recipients treated with tacrolimus who developed HLA-DR/DQ dnDSA had a higher proportion of tacrolimus trough levels <5 ng/ml, which continued to be significant after adjustment for HLA-DR/DQ eplet mismatch. Mean tacrolimus trough levels in the 6 months before dnDSA development were significantly lower than the levels >6 months before dnDSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developing dnDSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of dnDSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels <5 ng/ml unless essential, and monitoring for dnDSA may be advisable in this setting.
<i> <scp>KIT</scp> </i> mutations and <scp>CD</scp> 117 overexpression are markers of better progression‐free survival in vulvar melanomas
Authors: D. Dias‐Santagata, M.A. Selim, Y. Su, Y. Peng, R. Vollmer, A. Chłopik, G. Tell‐Marti, K.M. Paral, S.C. Shalin, C.R. Shea, S. Puig, M.T. Fernandez‐Figueras, W. Biernat, J. Ryś, A. Marszalek, M.P. Hoang
Journal: British Journal of Dermatology (2017)

Few studies have addressed prognostic markers and none has correlated molecular status and prognosis in vulvar melanomas.To evaluate the clinicopathological features of 95 cases of vulvar melanoma.p53, CD117, Ki-67, neurofibromin, brafv600e and nrasq61r immunostains, and molecular analyses by either targeted next-generation or direct sequencing, were performed on available archival materials.Molecular testing detected mutations in KIT (44%), BRAF (25%), NF1 (22%), TP53 (17%), NRAS (9%) and TERT promoter (9%). Co-mutation of KIT and NF1 and of KIT and NRAS were identified in two and one cases, respectively. KIT mutations were significantly associated with better progression-free survival in univariate analyses. In multivariate analyses CD117 expression was significantly associated with better progression-free survival. Tumour thickness was significantly associated with worse progression-free and overall survival, and perineural invasion significantly correlated with reduced melanoma-specific survival and reduced overall survival. Cases were from multiple centres and only a subset of samples was available for molecular testing.KIT mutations and CD117 overexpression are markers of better progression-free survival. In addition to its prognostic value, molecular testing may identify cases that might respond to targeted agents or immunotherapeutic approaches.