tbuckley/cabot-search huggingface dataset:
Characterization of chemoradiation-induced changes in immune cells and targets for personalized therapy in locally advanced rectal cancer (LARC).
Authors: Elisa Fontana, Anna Wilkins, Yatish Patil, Gift Nyamundanda, Chanthirika Ragulan, David Mansfield, Jennifer Kingston, Fiona Errington-Mais, Nicholas West, Daniel Bottomley, Jessica Downs, Sandra Demaria, Kevin Joseph Harrington, Alan Melcher, Anguraj Sadanandam
Journal: Journal of Clinical Oncology (2019)

589 Background: Neoadjuvant radio/chemoradiotherapy (CRT) is a treatment milestone for LARC. The importance of immune response in CRT efficacy is increasingly realised. However immune cell changes associated with poor responders and their modulation with immune-CRT combinations is unclear. Methods: Matched archival pre-CRT biopsies and post-CRT resection specimens from patients (pts) treated with neoadjuvant CRT were retrieved. Delta-TCD (tumor cell density, estimated using quantitative point counting on virtual tissue H&amp;E) and k-means clustering method were used to classify pts into good, intermediate and poor responders. Baseline expression and CRT-induced changes in 770 immune-related genes (plus 30 DNA damage response genes) were evaluated using NanoString Technologies. Results: At least 70 pts treated with short/long course radiotherapy (SCRT/LCRT) and matched tissues available were identified. To date, 27 pts evaluable for deltaTCD and gene expression were clustered into good (n:10), intermediate (n:7) and poor (n:10) responders. The expression of 14% (91/636) of immune genes was significantly affected by CRT (Bonferroni t-test, q-value &lt; 0.05) overall, with significant increase in innate immunity and decrease in adaptive immunity across all pts (CIBERSORT and SSGSEA analyses). Between good and poor responders there were 6% (39/636) and 2% (15/636) of genes significantly affected by CRT (Bonferroni t-test, q-value &lt; 0.05), respectively. CRT-induced increased CD8+ T cells expression in poor responders compared to good responders was seen. Increased baseline expression of resistance genes (including PD-L1, IDO1 and IL2RA) were seen in poor versus good responders. Validation with quantitative multiplex-immunofluorescence (Vectra) and correlation with SCRT/LCRT and time to surgery are on-going. Conclusions: The expression of immune-related genes is significantly modified by CRT in LARC. With the caveat of small numbers, we identified differentially expressed immune targets at baseline which may justify immune-CRT combinations in neoadjuvant setting in selected pts to modulate the CRT effect and ultimately increase response.
Abstract 18134: Importance of Fasting And Postprandial Triglycerides for Risk Prediction in Stable Coronary Disease - 24 Months Follow-up
Authors: Christian Werner, Angelika Knoll, Stefan Graeber, Michael Boehm, Ulrich Laufs
Journal: Circulation (2012)

Aim: Risk prediction with serum triglycerides (TG) in patients with cardiovascular disease remains uncertain. We examined the role of fasting and postprandial serum triglycerides as risk modifiers in relation to glucose metabolism and obesity in patients with coronary artery disease (CAD). Methods: A sequential oral triglyceride (OTT, 75g cream fat) and glucose tolerance test (OGT, 75g glucose) was applied to obtain standardized measurements of postprandial TG kinetics and glucose in 514 consecutive patients with stable CAD confirmed by angiography. Lipid and glucose parameters were measured at fasting, 3, 4, and 5 hours after the OTT/OGT. The primary outcome measure was the composite of cardiovascular death and cardiovascular hospitalizations. Here, the 24 months follow-up data are presented. Results: In the total cohort, fasting and postprandial TG did not correlate with the first primary outcome (log-rank test comparing TG tertiles, p=0.070 and 0.086, respectively). The total number of outcome events w...
Association of the Swiss Diagnosis-Related Group Reimbursement System With Length of Stay, Mortality, and Readmission Rates in Hospitalized Adult Patients
Authors: Alexander Kutz, Lara Gut, Fahim Ebrahimi, Ulrich Wagner, Philipp Schuetz, Beat Mueller
Journal: JAMA Network Open (2019)

In 2012, hospital reimbursement in Switzerland changed from a fee-for-service per diem system to a diagnosis-related group (SwissDRG) system. Whether this change in reimbursement is associated with harmful implications for quality of care and patient outcomes remains unclear.
First-Onset Herpesviral Infection and Lung Injury in Allogeneic Hematopoietic Cell Transplantation
Authors: Xiaofeng Zhou, David N. O’Dwyer, Meng Xia, Holly K. Miller, Paul R. Chan, Kelsey Trulik, Mathew M. Chadwick, Timothy C. Hoffman, Camille Bulte, Kevin Sekerak, Carol A. Wilke, Swapneel J. Patel, Wayne M. Yokoyama, Susan Murray, Gregory A. Yanik, Bethany B. Moore
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

"Noninfectious" pulmonary complications are significant causes of morbidity and mortality after allogeneic hematopoietic cell transplant. Early-onset viral reactivations or infections are common after transplant. Whether the first-onset viral infection causes noninfectious pulmonary complications is unknown.
Endoscopic intratumoral injection of OBP-301 (telomelysin) with radiotherapy in esophageal cancer patients unfit for standard treatments.
Authors: Shunsuke Tanabe, Hiroshi Tazawa, Nobuhiko Kanaya, Kazuhiro Noma, Shunsuke Kagawa, Shinji Kuroda, Yasuo Urata, Yasuhiro Shirakawa, Toshiyoshi Fujiwara
Journal: Journal of Clinical Oncology (2019)

130 Background: OBP-301 (telomelysin) is an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase (hTERT) promoter to regulate viral replication. OBP-301 causes selective replication and lysis of a variety of cancer cells, and also inhibits the repair of radiation-induced DNA double-strand breaks, leading to radiosensitization. We aimed to assess intratumoral injection of OBP-301 with radiotherapy in esophageal cancer patients unfit for standard treatments. Methods: An open-label, phase I dose-escalation study of OBP-301 with radiotherapy was conducted in 13 histologically confirmed esophageal cancer patients who deemed unfit to receive surgery or chemotherapy. Study treatment consisted of intratumoral OBP-301 injections on days 1, 18, and 32 of treatment. Radiation therapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy. Virus administration was performed by intratumoral needle injection of the primary tumor through a flexible endoscope. The primary and secondary end points were incidence of dose-limiting toxicities and objective response rate. Results: Of 13 patients, seven, three, and three patients were treated in the cohorts with 10 10 , 10 11 , and 10 12 virus particles of OBP-301, respectively. The patients comprised 10 males and 3 females, with median age of 79.7 years (range, 53 to 92 years). Common grade 1 and 2 toxicities included fever, esophagitis, pneumonitis, anorexia, constipation, and gastroesophageal reflux. All patients developed a transient, self-limited lymphopenia. Eight patients had local complete response (CR); all of them exhibited pathologically no viable malignant cells in biopsy specimens, and three had partial response. The objective response rate was 84.6%. The clinical CR rate was 80.0% in stage I and 66.7% in stage II/III, respectively. Histopathologic examination in post-treatment specimens showed massive infiltration of CD8 + cells in three partially responded tumors. Conclusions: Multiple courses of endoscopic OBP-301 injection with radiotherapy were feasible and provided definite clinical benefits in patients with esophageal cancer. Clinical trial information: 000010158.
A retrospective analysis of neoadjuvant chemotherapy followed by surgery or definitive chemoradiotherapy in patients with advanced esophageal squamous cell carcinoma.
Authors: Hiroshi Nakatsumi, Yoshito Komatsu, Shintaro Nakano, Kentaro Sawada, Tetsuhito Muranaka, Yasuyuki Kawamoto, Satoshi Yuki, Yusuke Uchinami, Hiroshi Taguchi, Hiroki Shirato, Yuma Ebihara, Toshiaki Shichinohe, Satoshi Hirano, Naoya Sakamoto
Journal: Journal of Clinical Oncology (2019)

115 Background: The standard treatment of resectable esophageal cancer in Japan is neoadjuvant chemotherapy (NAC) followed by surgery, while definitive chemoradiotherapy (CRT) is considered as an alternative treatment. There are no randomized clinical trials comparing NAC and CRT in Japan. The aim of this study was to evaluate the efficacy of NAC or CRT in clinical practice. Methods: We retrospectively analyzed the clinical data of 43 patients (pts) with clinical stage IB/II/III thoracic esophageal squamous cell carcinoma (ESCC) who received NAC (n = 26) or CRT (n = 17) in Hokkaido University Hospital from January 2009 to December 2014. To compare NAC with CRT, Fisher’s exact test or Mann-Whitney U test was used in terms of pts’ characteristics, and Log-rank test was used in progression-free survival (PFS) and overall survival (OS). Results: Pts’ characteristics were as follows; Gender (male/female): 24/2 in NAC and 16/1 in CRT, median age (range): 65y (55-78) in NAC and 72y (57-80) in CRT, primary lesion (Ut/Mt/Lt): 4/12/10 in NAC and 2/9/6 in CRT, clinical stage IB-II/III: 11/15 in NAC and 9/8 in CRT. Four pts (15.4%) in NAC and seven pts (41.2%) in CRT had multiple primary cancer. All pts in NAC and 15 pts in CRT received 5-FU+cisplatin (CDDP), and two pts in CRT received 5-FU+nedaplatin. RT dose in CRT was 50.4Gy in 11 pts, 59.4Gy in five pts and 60Gy in one patient. Four out of 10 pts in NAC with local recurrence received salvage CRT, and three out of 10 pts in CRT with local recurrence received salvage surgery. Median PFS was 21.6 months in NAC and 8.7 months in CRT (HR 1.282, 95% confidence interval (CI) 0.871-1.887, p = 0.203), and median OS was 50.4 months in NAC and 48.6 months in CRT (HR 1.151, 95% CI 0.752-1.761, p = 0.516). 5-year OS rate was 49.7% in NAC and 48.3% in CRT. Conclusions: Definitive CRT showed comparable outcome to NAC followed by surgery in pts with resectable thoracic ESCC. Efficacy of NAC or CRT were not sufficient compared to clinical trials. Improvement in efficacy by development of optimal multimodality therapy was warranted.
The Yield and Safety of Screening Colonoscopy in Patients Evaluated for Liver Transplantation
Authors: Rosalie C. Oey, Laurelle van Tilburg, Nicole S. Erler, Herold J. Metselaar, Manon C.W. Spaander, Henk R. van Buuren, Robert A. de Man
Journal: Hepatology (2019)

Colorectal cancer (CRC) screening with colonoscopy is commonly used in patients who are candidates for liver transplantation. We initiated this study to define the risk‐benefit ratio of performing screening colonoscopy in this population. A retrospective observational study of all consecutive patients undergoing colonoscopy during pre–liver transplantation screening between 2004 and 2017 was conducted. Endoscopic and pathological findings and clinical events potentially related to the colonoscopy in the 30 days after the procedure were registered and compared with a 30‐day inpatient control time frame. A total of 858 colonoscopies were performed in 808 patients (65% male; median age, 55 years [interquartile range (IQR), 47‐62]; median model for end‐stage liver disease (MELD) score, 15 [IQR, 11‐18]). CRC was found in 2 patients (0.2%), and advanced adenomas were found in 44 patients (5.4%). The only independent risk factor for an advanced neoplasm was age (odds ratio, 1.072 per year; 95% confidence interval, 1.031‐1.115; P &lt; 0.001). During the 30‐day postprocedure period, 178 clinical events occurred in 128 patients compared with 101 clinical events in 72 patients in the control time frames ( P &lt; 0.001). After colonoscopy, there was a significantly increased risk for renal failure ( P = 0.001) and gastrointestinal (GI) bleeding ( P = 0.023). Presence of ascites and MELD score were identified as independent risk factors for acute renal failure and GI bleeding. During the study observation period, 53.5% of the screened population actually underwent liver transplantation. Conclusion : CRC screening in pre–liver transplantation patients is associated with a relatively low prevalence of CRC and an increased risk of postcolonoscopy complications such as acute renal failure and GI bleeding, especially in patients with advanced liver disease. Because the risk‐benefit ratio of standard performance of a screening colonoscopy in this population appears questionable, alternative screening strategies should be considered.
Red Cell Alloimmunisation Is Associated with Increased Red Cell Transfusion Requirements in Myelodysplastic Syndrome
Authors: Rakchha Chhetri, Amilia Wee, Romi Sinha, Monika M Kutyna, Soumya Gupta, Lakshmi Nath, Shriram V. Nath, Nicholas Wickham, Ian D Lewis, David M Ross, Luen Bik To, Deepak Singhal, David John Roxby, Devendra K Hiwase
Journal: Blood (2018)
Site-specific conjugation of recognition tags to trastuzumab for peptide nucleic acid-mediated radionuclide HER2 pretargeting
Authors: Kristina Westerlund, Anzhelika Vorobyeva, Bogdan Mitran, Anna Orlova, Vladimir Tolmachev, Amelie Eriksson Karlström, Mohamed Altai
Journal: Biomaterials (2019)

Pretargeting is a promising strategy to reach high imaging contrast in a shorter time than by targeting with directly radiolabeled monoclonal antibodies (mAbs). One of problems in pretargeting is a site-specific, reproducible and uniform conjugation of recognition tags to mAbs. To solve this issue we propose a photoconjugation to covalently couple a recognition tag to a mAb via a photoactivatable Z domain. The Z-domain, a 58-amino acid protein derived from the IgG-binding B-domain of Staphylococcus aureus protein A, has a well-characterized binding site in the Fc portion of IgG. We tested the feasibility of this approach using pretargeting based on hybridization between peptide nucleic acids (PNAs). We have used photoconjugation to couple trastuzumab with the PNA-based hybridization probe, HP1. A complementary [57Co]Co-labeled PNA hybridization probe ([57Co]Co-HP2) was used as the secondary targeting probe. In vitro studies demonstrated that trastuzumab-ZHP1 bound specifically to human epidermal growth factor receptor 2 (HER2)-expressing cells with nanomolar affinity. The binding of the secondary [57Co]Co-HP2 probe to trastuzumab-PNA-pretreated cells was in the picomolar affinity range. A two-fold increase in SKOV-3 tumor targeting was achieved when [57Co]Co-HP2 (0.7 nmol) was injected 48 h after injection of trastuzumab-ZHP1 (0.5 nmol) compared with trastuzumab-ZHP1 alone (0.8 ± 0.2 vs. 0.33 ± 0.06 %ID/g). Tumor accumulation of [57Co]Co-HP2 was significantly reduced by pre-saturation with trastuzumab or when no trastuzumab-ZHP1 was preinjected. A tumor-to-blood uptake ratio of 1.5 ± 0.3 was achieved resulting in a clear visualization of HER2-expressing xenografts as confirmed by SPECT imaging. In conclusion, the feasibility of stable site-specific coupling of a PNA-based recognition tag to trastuzumab and successful pretargeting has been demonstrated. This approach can hopefully be used for a broad range of mAbs and recognition tags.
Population Pharmacokinetic/Pharmacodynamic Modelling Reveals A Positive Relationship Between Complement 4 Serum Antigen Concentrations And C1 Inhibitor Functional Activity Levels
Authors: Bruce L. Zuraw, Sandra C. Christiansen, Timothy Craig, Hilary Longhurst, Marco Cicardi, Joseph Chiao, Ingo Pragst, Dipti Pawaskar
Journal: Journal of Allergy and Clinical Immunology (2019)

While the relationship between hereditary angioedema (HAE) attack risk and C1-INH functional activity (C1-INH[f]) is well established, its relation to complement 4 (C4) serum antigen concentrations—which are low in HAE and thus a potential disease activity biomarker—is unknown. This analysis aimed to quantify this relationship using a population pharmacokinetic/pharmacodynamic (PK/PD) model in HAE patients. C1-INH(f) and C4 antigen concentrations were measured in three trials (NCT01912456, NCT01576523, NCT02316353 [COMPACT Phase 2, 3 and open-label extension studies]), their correlation visually evaluated, and a population PK/PD model developed (NONMEM v7.3). The previously developed model was used to describe the PK of C1-INH(f) after subcutaneous administration of C1-INH to HAE patients. Several PD models were tested to describe the relationship between C1-INH(f) and C4 antigen concentrations. A positive linear relationship was observed between C4 antigen concentrations and C1-INH(f) in type I and II HAE patients based on the Loess fit until C1-INH(f) of ∼50%, at which point signs of saturation were apparent. A mechanistic quantification of this relationship was established with the indirect response model with C1-INH causing inhibition of the loss of C4 (rate of loss= kout) showing best performance in data characterization. Baseline C4 antigen concentration was estimated at 7.52 mg/dL (29.4% inter-individual variability). The IC50 was estimated at 56.3% C1-INH. No covariates were found to be significant to describe the parameter variability. The relationship between C1-INH(f) and C4 antigen concentrations in HAE patients was adequately described by a mechanistically accurate indirect response model with inhibition of removal process.
Abstract MP067: Reducing US Cardiovascular Disease Disparities Through Dietary Policy
Authors: Jonathan Pearson-Stuttard, Piotr Bandosz, Colin D Rehm, Jose Penalvo, Laurie Whitsel, Tom Gaziano, Zach Conrad, Parke Wilde, Renata Micha, Ffion Lloyd-Williams, Simon Capewell, Dariush Mozaffarian, Martin O’Flaherty
Journal: Circulation (2017)

Quantifying reductions in US cardiovascular deaths and disparities by different diet policies Background: Large disparities exist in US dietary habits and cardiovascular disease (CVD) mortality. While economic incentives have demonstrated success in improving dietary choices, the quantitative impact of different dietary policies on CVD disparities is not well-established Methods: Using a US IMPACT Food Policy Model and probabilistic sensitivity analyses, we estimated and compared the reductions in CVD mortality and disparities in the US population potentially achievable from 2015 to 2030 with specific dietary policy scenarios a) a national mass media campaign (Media campaign) aimed to increase consumption of fruits and vegetables (F&amp;V) or reduce sugar sweetened beverages (SSBs), b) national fiscal policies to tax SSB and increase price by 10% and subsidize F&amp;V to reduce prices by 10%; and c) a targeted policy, to subsidize F&amp;V to reduce prices by 30% among Supplemental Nutrition Assistance Programme (SNAP) participants only. We also evaluated a combined multi-component approach, combining each of the above policies. Results: Among individual policy options, a national 10% F&amp;V subsidy was estimated to be most effective, resulting in approximately 150,500 (95% CI, 142,700-157,900) CVD deaths potentially prevented or postponed (DPPs) by 2030. This far exceed the approximately 35,100 (32,000-37,900) DPPs from a 30% F&amp;V subsidy targeting SNAP participants, or some 23,000 (21,700-24,600) DPPs from a 1-year Media campaign or approximately 21,400 (19,500-23,600) DPPs from a 10% SSB tax. Neither the Media campaign nor individual national economic policies would significantly reduce CVD disparities. However, the SNAP-targeted intervention would significantly reduce CVD disparities between SNAP participants and SNAP-ineligible individuals, by approximately 7% (10 DPPs per 100,000 population). The combined policy approach would save more lives than any single policy studied (approximately 215,500 DPPs by 2030) while also significantly reducing disparities by approximately 5% (7 DPPs per 100,000 population). Conclusions: Fiscal strategies targeting diet could reduce CVD burdens. A national 10% F&amp;V subsidy would save by far the most lives, while a SNAP-targeted 30% F&amp;V subsidy would most reduce disparities. A combined policy would have the greatest overall impact on both mortality and disparities.
Synergistic suppression of T cell-induced eosinophilia by glucocorticoid and CTLA4-Ig
Authors: Mori Akio, Satoshi Kouyama, Miyako Yamaguchi, Chiemi Kumitani, Akemi Ohtomo-Abe, Norihiko Fujita, Maki Iwata, Kisako Nagayama, Kai Ryu, Yuto Nakamura, Yasuhiro Tomita, Yuto Hamada, Hiroaki Hayashi, Kentaro Watai, Yosuke Kamide, Kiyoshi Sekiya, Yuma Fukutomi, Masami Taniguchi, Takayuki Ohtomo, Osamu Kaminuma
Journal: Journal of Allergy and Clinical Immunology (2019)
Pan-HDAC Inhibitors May Restore PRDM1 Expression in Follicular Lymphoma
Authors: Thierry Fest, Fabienne Desmots-Loyer, Mikael Roussel, Celine Pangault, Cedric Pastoret, Francisco Llamas-Gutierrez, Eric Guiheneuf, Valérie Camara-clayette, Thierry Lamy, Karin Tarte, Vincent Ribrag
Journal: Blood (2018)
Immunome Single Cell Profiling Reveals T Cell Exhaustion with Upregulation of Checkpoint Inhibitors LAG3 and Tigit on Marrow Infiltrating T Lymphocytes in Daratumumab and IMiDs Resistant Patients
Authors: Paola Neri, Ranjan Maity, Ines Tagoug, Sylvia McCulloch, Peter Duggan, Victor Jimenez-Zepeda, Jason Tay, Anjan Thakurta, Nizar Bahlis
Journal: Blood (2018)
Cell–cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models
Authors: Yanhong Li, Di Zhang, Ling Xu, Lin Dong, Ji Zheng, Yikong Lin, Jiefang Huang, Yanyun Zhang, Yu Tao, Xingxing Zang, Dajin Li, Meirong Du
Journal: Cellular and Molecular Immunology (2019)
Response to: ‘Prevention of infections in patients with antineutrophil cytoplasm antibody-associated vasculitis: potential role of hydroxychloroquine’ by Novikov<i>et al</i>
Authors: Andreas Kronbichler, David Jayne
Journal: Annals of the Rheumatic Diseases (2019)

We thank Dr Novikov et al for their letter on the risk of infections of patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis and the proposed beneficial effects of hydroxychloroquine (HCQ) to reduce severe infections, as a response to our recently published article ‘Trimethoprim-sulfamethoxazole prophylaxis prevents severe/life-threatening infections following rituximab in antineutrophil cytoplasm antibody-associated vasculitis’.1 2 

Modern therapies and adoption of treatment protocols have improved outcome of patients with ANCA-associated vasculitis. Morbidity and mortality, either attributable to the disease or immunosuppressive measures, remain a challenge for the treating physician. A recent meta-analysis of observational studies found a 2.7-fold increased risk of death with a trend towards improved mortality rates in more recent cohorts.3 Among patients recruited into the ‘early trials’ conducted by the European Vasculitis Society (EUVAS), 133 (25%) deaths were recorded over a median follow-up period of 5.2 years. Main causes for death were infections (48%) and active vasculitis (19%) in the first year, while infectious complications remained one of the leading complications leading to mortality (20%) thereafter. Moreover, infections were the leading contributing factor of mortality in this period.4 Several risk factors leading to infections have been identified in …
68Ga-PSMA Uptake in Prostate Cancer Sciatic Nerve Metastasis
Authors: Patrícia Barros Gouveia, Liliana Catarina Sobral Violante, Ricardo Jorge Valpaços Teixeira, Luís Hugo da Silva Trindade Duarte
Journal: Clinical Nuclear Medicine (2019)

Abstract Most prostate cancers spread to regional lymph nodes, axial skeleton and lungs. Perineural malignant involvement is very rare. We present a 68 Ga-PSMA PET/CT image of a sciatic nerve metastasis in a 65-year-old man with recurrent prostate cancer.