tbuckley/cabot-search huggingface dataset:
Evidence for a field effect in early prostate cancer (PCa): Gene expression profiles in normal-appearing prostate tissue (NT) adjacent to tumor (T) as predictors of clinical outcome.
Authors: Eric A. Klein, Sara Moscovita Falzarano, Nan Zhang, Dejan Knezevic, Tara Maddala, H. Jeffrey Lawrence, Diana B. Cherbavaz, Robert J. Pelham, Carl Millward, Mark Lee, Cristina Magi-Galluzzi
Journal: Journal of Clinical Oncology (2013)

5029 Background: We previously identified genes whose expression predicts aggressive PCa (clinical recurrence (cR), prostate cancer death (PCD), adverse pathology) when assessed in histologically heterogeneous tumor foci and in biopsies (Klein ASCO 2012). These results enabled the definition of a multi-gene Genomic Prostate Score (GPS), which has been clinically validated (Cooperberg AUA 2013). There is interest regarding a possible field effect in PCa, i.e. molecular alterations throughout the gland that may influence PCa development. We conducted exploratory analyses to evaluate gene expression, including GPS, in adjacent normal-appearing tissue (NT) for prediction of cR and PCD. Methods: Cohort sampling was used to select 127 patients with and 374 without cR from 2,641 patients treated with RP for T1/T2 PCa. Expression of 732 genes was measured by qRT-PCR separately in T and NT (defined as &gt; 3 mm from T) specimens. GPS (0-100 units) was determined using the genes and algorithm from the validation study. Analysis used Cox proportional hazards models and Storey’s false discovery rate (FDR) control. Results: 410 evaluable patients had paired T and NT. Of the 405 genes which were predictive of outcome in T (FDR &lt; 20%), 289 (71%) showed similar but weaker effects in NT. 47 genes were associated with cR in NT (FDR &lt; 20%), of which 34 also concordantly predicted cR in T (FDR &lt; 20%). GPS assessed in NT significantly predicted time to cR (HR/20 units = 1.8; 95% CI: 1.3-2.4; p&lt; 0.001) and PCD (HR/20 units = 1.9; 95% CI: 1.2-3.0; p = 0.005) but was less predictive than GPS in T (HR/20 units = 4.8 for cR; 95% CI: 3.7-6.2; p &lt; 0.001 and HR/20 units = 6.9 for PCD; 95% CI: 4.4-10.7; p &lt; 0.001). The strongest components of GPS in predicting cR and PCD in NT were stromal response and androgen signaling genes (p &lt; 0.05); proliferation and cellular organization genes did not consistently provide a significant contribution in NT. Conclusions: These data indicate that gene expression profiles, including GPS, can predict outcome in NT, albeit more weakly than in tumor. These findings suggest that there is an underlying field effect associated with the development of aggressive PCa.
The Evolving Paradigm of Prostate Cancer Screening
Authors: Peter C. Albertsen
Journal: JAMA Network Open (2019)

Martha M. C. Elwenspoek, PhD; Athena L. Sheppard, MSc; Matthew D. F. McInnes, MD, PhD; Samuel W. D. Merriel, MSc; Edward W. J. Rowe, MD; Richard J. Bryant, FRCS(Urol), PhD; Jenny L. Donovan, PhD; Penny Whiting, PhD
TLR9 signaling in fibroblastic reticular cells regulates peritoneal immunity
Authors: Li Xu, Yiming Li, Chenxuan Yang, Patricia Loughran, Hong Liao, Rosemary Hoffman, Timothy R. Billiar, Meihong Deng
Journal: Journal of Clinical Investigation (2019)

Fibroblastic reticular cells (FRCs), a subpopulation of stromal cells in lymphoid organs and fat-associated lymphoid clusters (FALCs) in adipose tissue, play immune-regulatory roles in the host response to infection and may be useful as a form of cell therapy in sepsis. Here, we found an unexpected major role of TLR9 in controlling peritoneal immune cell recruitment and FALC formation at baseline and after sepsis induced by cecal ligation and puncture (CLP). TLR9 regulated peritoneal immunity via suppression of chemokine production by FRCs. Adoptive transfer of TLR9-deficient FRCs more effectively decreased mortality, bacterial load, and systemic inflammation after CLP than WT FRCs. Importantly, we found that activation of TLR9 signaling suppressed chemokine production by human adipose tissue–derived FRCs. Together, our results indicate that TLR9 plays critical roles in regulating peritoneal immunity via suppression of chemokine production by FRCs. These data form a knowledge basis upon which to design new therapeutic strategies to improve the therapeutic efficacy of FRC-based treatments for sepsis and immune dysregulation diseases.
Computational modelling prediction and clinical validation of impact of benralizumab on airway smooth muscle mass in asthma
Authors: Latifa Chachi, Sarah Diver, Himanshu Kaul, Marlon C. Rebelatto, Anmarie Boutrin, Patricia Nisa, Paul Newbold, Christopher Brightling
Journal: European Respiratory Journal (2019)

Asthma is a heterogeneous condition characterised by chronic inflammation and airway remodelling. T2-mediated airway inflammation, characterised by interleukin (IL)-4, IL-5 and IL-13, has been the recent focus of pharmacotherapy, with a host of targeted biologic agents now available to clinicians [1]. The anti-IL-5 receptor agent, benralizumab, causes depletion of eosinophils and basophils via antibody-dependent cell-mediated cytotoxicity in blood; however, the mechanism of action in the tissue is uncertain. Benralizumab has reduced exacerbations and improved lung function in clinical trials. Benralizumab leads to a reduction in ASM mass in asthmatic airways, which can be predicted using a computational model <http://bit.ly/2OwNMBy>
Host–Guest Polypyrrole Nanocomplex for Three‐Stimuli‐Responsive Drug Delivery and Imaging‐Guided Chemo‐Photothermal Synergetic Therapy of Refractory Thyroid Cancer
Authors: Xiaotu Ma, Xiaoda Li, Jiyun Shi, Meinan Yao, Xu Zhang, Rui Hou, Nan Shao, Qi Luo, Yu Gao, Shuaifan Du, Xiaolong Liang, Fan Wang
Journal: Advanced Healthcare Materials (2019)

Abstract Despite the good prognosis of the low‐risk thyroid cancer, there are no truly effective treatments for radioactive iodine‐refractory thyroid cancer. Herein, a novel theranostic nanoplatform, as well as a smart doxorubucin (DOX) delivery system is fabricated. Gelatin‐stabilized polypyrrole nanoparticles are reported for the first time. The combination of gelatin‐stabilized polypyrrole and cyclodextrin‐DOX complexes enabling three‐stimuli‐controlled drug delivery, including the enzyme‐sensitive, pH‐sensitive and photothermal‐sensitive drug release, exhibiting a new way to equip photothermal agents with precisely controlled drug delivery. Anti‐galectin‐3 antibodies are utilized as the targeting molecules of nanoparticles in the first time, which surprisingly increase intracellular DOX uptake by enhanced clathrin‐mediated endocytosis, showing galectin‐3 can be employed as a highly efficient target of drug delivery systems. The nanoparticles achieve excellent photoacoustic imaging effect, enabled chemo‐photothermal combined therapy with pinpointed drug delivery. Compared to free DOX, these multifunctional nanoparticles decrease the heart damage, but greatly increase the tumor/heart ratio of DOX concentration by 12.9‐fold. The tumors are completely eradicated without any recurrence after the in vivo combined therapy. To the best of the authors' knowledge, this is also the first report to apply photoacoustic imaging‐guided chemo‐photothermal therapy for thyroid cancer, showing great potential to solve the dilemma in thyroid cancer therapy.
A 24‐week multicentre, randomized, open‐label, parallel‐group study comparing the efficacy and safety of ixekizumab vs. fumaric acid esters and methotrexate in patients with moderate‐to‐severe plaque psoriasis naive to systemic treatment
Authors: K. Reich, M. Augustin, D. Thaçi, A. Pinter, A. Leutz, C. Henneges, E. Schneider, A. Schacht, M. Dossenbach, U. Mrowietz
Journal: British Journal of Dermatology (2019)

Interleukin-17 antagonists have received a first-line label for moderate-to-severe plaque psoriasis.We conducted the first head-to-head trial between the two most commonly used first-line therapies in Germany, fumaric acid esters (FAEs) and methotrexate, and the interleukin-17A antagonist, ixekizumab.Systemic-naive patients were randomized in this parallel-group, active-comparator, open-label, rater-blinded trial (each group n = 54). The primary outcome was the proportion of patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at 24 weeks. Key secondary outcomes included 24-week PASI 90 and 100, static Physician's Global Assessment (sPGA) score of 0 or 1, and Dermatology Life Quality Index (DLQI) score of 0 or 1. Safety events at week 24 were analysed using Fisher's exact test. Missing data were imputed using nonresponder imputation. The trial was registered at ClinicalTrials.gov (NCT02634801) and EudraCT (2015-002649-69).At week 24, more ixekizumab-treated patients achieved PASI 75 [91% vs. 22% FAEs (P < 0·001) and 70% methotrexate (P = 0·014)], PASI 90 [80% vs. 9% FAEs (P < 0·001) and 39% methotrexate (P < 0·001)] and PASI 100 [41% vs. 4% FAEs (P < 0·001) and 13% methotrexate (P = 0·0041)], as well as sPGA (0,1) and DLQI (0,1).Ixekizumab was superior in inducing PASI 75/90/100, sPGA (0,1) and DLQI (0,1) responses at week 24 compared with methotrexate and FAEs. Safety profiles for all treatments were consistent with prior studies.
Post-Transplant Cyclophosphamide (PT-Cy) for Graft Versus Host Disease (GVHD) Prophylaxis in Allogeneic Transplantation from HLA Identical Sibling and Matched Unrelated Donor for Patients with Acute Leukemia, on Behalf of ALWP-EBMT
Authors: Annalisa Ruggeri, Myriam Labopin, Boris V Afanasyev, Jan J Cornelissen, Ahmet Elmaagacli, Maija Itälä-Remes, Didier Blaise, Ellen Meijer, Koc Yener, Noel Milpied, Harry C. Schouten, Nicolaus Kröger, Mohamad Mohty, Andrea Bacigalupo, Arnon Nagler
Journal: Blood (2017)
Maximal Recruitment Open Lung Ventilation in Acute Respiratory Distress Syndrome (PHARLAP). A Phase II, Multicenter Randomized Controlled Clinical Trial
Authors: Carol L. Hodgson, D. James Cooper, Yaseen Arabi, Victoria King, Andrew Bersten, Shailesh Bihari, Kathy Brickell, Andrew Davies, Ciara Fahey, John Fraser, Shay McGuinness, Lynne Murray, Rachael Parke, Eldho Paul, David Tuxen, Shirley Vallance, Meredith Young, Alistair Nichol
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Open lung ventilation strategies have been recommended in patients with acute respiratory distress syndrome (ARDS).Objectives: To determine whether a maximal lung recruitment strategy reduces ventilator-free days in patients with ARDS.Methods: A phase II, multicenter randomized controlled trial in adults with moderate to severe ARDS. Patients received maximal lung recruitment, titrated positive end expiratory pressure and further Vt limitation, or control "protective" ventilation.Measurements and Main Results: The primary outcome was ventilator-free days at Day 28. Secondary outcomes included mortality, barotrauma, new use of hypoxemic adjuvant therapies, and ICU and hospital stay. Enrollment halted October 2, 2017, after publication of ART (Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial), when 115 of a planned 340 patients had been randomized (57% male; mean age, 53.6 yr). At 28 days after randomization, there was no difference between the maximal lung recruitment and control ventilation strategies in ventilator-free days (median, 16 d [interquartile range (IQR), 0-21 d], n = 57, vs. 14.5 d [IQR, 0-21.5 d], n = 56; P = 0.95), mortality (24.6% [n = 14/56] vs. 26.8% [n = 15/56]; P = 0.79), or the rate of barotrauma (5.2% [n = 3/57] vs. 10.7% [n = 6/56]; P = 0.32). However, the intervention group showed reduced use of new hypoxemic adjuvant therapies (i.e., inhaled nitric oxide, extracorporeal membrane oxygenation, prone; median change from baseline 0 [IQR, 0-1] vs. 1 [IQR, 0-1]; P = 0.004) and increased rates of new cardiac arrhythmia (n = 17 [29%] vs. n = 7 [13%]; P = 0.03).Conclusions: Compared with control ventilation, maximal lung recruitment did not reduce the duration of ventilation-free days or mortality and was associated with increased cardiovascular adverse events but lower use of hypoxemic adjuvant therapies.Clinical trial registered with www.clinicaltrials.gov (NCT01667146).
Retrospective analysis of pathological response in colorectal cancer liver metastases following treatment with bevacizumab: Updated findings.
Authors: Ruth Vera, Joan Figueras, Marisa Gomez Dorronsoro, Santiago Lopez Ben, Antonio Viudez, Bernardo Queralt, Irene Hernandez, Jordi Soriano, Cruz Zazpe, Rosa Maria Ortiz Duran
Journal: Journal of Clinical Oncology (2012)

e14120 Background: Recent reports have shown that pathological response predicts for better outcome (overall survival) following preoperative chemotherapy and surgical resection of colorectal cancer (CRC) liver metastases. The aim of this retrospective analysis was to evaluate the effect of adding bevacizumab (BEV) to standard chemotherapy on pathological response in patients (pts) with CRC liver metastases. Methods: Pts with stage IV CRC with liver metastases who received neoadjuvant chemotherapy (oxaliplatin-or irinotecan-based) at two Spanish centres were analysed retrospectively. Pathological response was evaluated as follows: complete pathological response (cPR), PR1 (&lt;25% of residual viable tumour cells), PR2 (25–50% of residual tumour), PR3 (&gt;50% of residual tumour). cPR or PR1 was considered to be a good response, and PR2 or PR3 a poor response. KRAS status was determined from tumour blocks. Results: 95 pts were evaluated. Of these, 44 received chemotherapy alone and 51 received chemotherapy + BEV. Baseline characteristics were as follows: median age 61.0 years (range 43.0–80.0 years); male/female (68%/32%); tumour location – colon (72%) / rectum (28%); hepatic metastases – synchronous (74%) / metachronous (26%); extrahepatic disease – yes (26%) / no (74%); KRAS status – mutated (37%) / wild type (29%) / not available (34%). The overall response rate (ORR) by RECIST was 51% (1 CR and 47 PRs) and 48% of pts had stable disease. ORR did not appear to vary in pts who did or did not receive BEV. In terms of pathological response, 49% of pts receiving BEV had a good response (cPR + PR1) compared with 27% of those receiving chemotherapy alone (p=0.0302). Good pathological response (cPR + PR1) was slightly lower in pts with mutant (31%) vs wild type (43%) KRAS status (difference not significant). At the end of the analysis, 45% of pts had relapsed and 67% were alive. Conclusions: Adding BEV to standard chemotherapy in the neoadjuvant setting improves pathological response of liver metastases in pts with stage IV CRC. Further studies are required to examine the potential relationship between pathological response and survival outcomes in pts with CRC and liver metastases.
Palliative chemotherapy in advanced colorectal cancer patients age 80 or older.
Authors: Pamela Lai, Shelly Sud, Tinghua Zhang, Timothy R. Asmis, Paul Wheatley-Price
Journal: Journal of Clinical Oncology (2013)

e14598 Background: Colorectal cancer (CRC) is the second most common cancer worldwide, with a median age at diagnosis of 71 years. While there has been significant progress in chemotherapy (CT) options for metastatic CRC (mCRC) patients (pts) over the past decade, there is very little data on outcomes or toxicity from CT in mCRC pts aged ≥80 years. We investigated palliative CT in the 80+ mCRC population, hypothesizing that high rates of hospitalization and toxicity may be observed. Methods: With ethics approval, a retrospective chart review was conducted of pts ≥80 years with mCRC who initiated a CT course between June 2005 and November 2009 at our institution. Baseline data on pt demographics were collected, in addition to CT data. The endpoints included: rates of hospitalization, CT discontinuation due to toxicity, and overall survival (OS). Results: CT was initiated on 88 occasions during the study period. The median age was 83 (range 80-92) and 52% of pts were male. Where data were available, 60% of pts had a good performance status (PS) of ECOG 0-1, 20% PS 2 and 9% PS 3 (10% unknown). 63 pts (72%) lived with family and 23% lived alone. 76% had a Charlson Comorbidity Index (CCI) ≥7 and 31% were taking ≥6 baseline prescription medications. At baseline, 33% of pts were anemic (Hgb &lt;100), 36% had leukocytosis (WBC&gt;11) and 48% had renal impairment (eGFR &lt;60). Palliation was the intent for 95% of cases and 47 pts (53%) were receiving first line CT. The initial CT dose was adjusted from standard of care in 67% of cases. The most common CT was capecitabine monotherapy (45%). In total 19 pts (22%) were hospitalized during or within 30 days of CT; 26 pts (30%) discontinued CT due to toxicity, and 48 pts (55%) required at least 1 dose reduction, delay or omission. The median OS was 14.6 months (95% CI 11.7-18.6). No baseline factors (age, sex, PS, CCI, line of CT, baseline dose adjustment, baseline blood work) were associated with hospitalization, CT discontinuation due to toxicity, or OS. Conclusions: Palliative CT for mCRC in the ≥80 population is feasible, but most pts will require dose adjustments, and a significant minority will be hospitalized or stop CT due to toxicity. Prospective research incorporating geriatric assessment tools is required.
Class-Switch Recombination Occurs Infrequently in Germinal Centers
Authors: Jonathan A. Roco, Luka Mesin, Sebastian C. Binder, Christian Nefzger, Paula Gonzalez-Figueroa, Pablo F. Canete, Julia Ellyard, Qian Shen, Philippe A. Robert, Jean Cappello, Harpreet Vohra, Yang Zhang, Carla R. Nowosad, Arien Schiepers, Lynn M. Corcoran, Kai-Michael Toellner, Jose M. Polo, Michael Meyer-Hermann, Gabriel D. Victora, Carola G. Vinuesa
Journal: Immunity (2019)
Association of Levels of Specialized Care With Risk of Premature Mortality in Patients With Epilepsy
Authors: Mark W. Lowerison, Colin B. Josephson, Nathalie Jetté, Tolulope T. Sajobi, Scott Patten, Tyler Williamson, Rob Deardon, Herman W. Barkema, Samuel Wiebe
Journal: JAMA Neurology (2019)

<h3>Importance</h3> Patients with epilepsy are at an elevated risk of premature mortality. Interventions to reduce this risk are crucial. <h3>Objective</h3> To determine if the level of care (non-neurologist, neurologist, or comprehensive epilepsy program) is negatively associated with the risk of premature mortality. <h3>Design, Setting, and Participants</h3> In this retrospective open cohort study, all adult patients 18 years or older who met the administrative case definition for incident epilepsy in linked databases (Alberta Health Services administrative health data and the Comprehensive Calgary Epilepsy Programme Registry [CEP]) inclusive of the years 2002 to 2016 were followed up until death or loss to follow-up. The final analyses were performed on May 1, 2019. <h3>Exposures</h3> Evaluation by a non-neurologist, neurologist, or epileptologist. <h3>Main Outcomes and Measures</h3> The outcome was all-cause mortality. We used extended Cox models treating exposure to a neurologist or the CEP as time-varying covariates. Age, sex, socioeconomic deprivation, disease severity, and comorbid burden at index date were modeled as fixed-time coefficients. <h3>Results</h3> A total 23 653 incident cases were identified (annual incidence of 89 per 100 000); the mean age (SD) at index date was 50.8 (19.1) years and 12 158 (50.3%) were women. A total of 14 099 (60%) were not exposed to specialist neurological care, 9554 (40%) received care by a neurologist, and 2054 (9%) received care in the CEP. In total, 4098 deaths (71%) occurred in the nonspecialist setting, 1481 (26%) for those seen by a neurologist, and 176 (3%) for those receiving CEP care. The standardized mortality rate was 7.2% for the entire cohort, 9.4% for those receiving nonspecialist care, 5.6% for those seen by a neurologist, and 2.8% for those seen in the CEP. The hazard ratio (HR) of mortality was lower in those receiving neurologist (HR, 0.85; 95% CI, 0.77-0.93) and CEP (HR, 0.49; 95% CI, 0.38-0.62) care. In multivariable modeling, specialist care, the age at index, and disease severity were retained in the final model of the association between specialist care and mortality. <h3>Conclusions and Relevance</h3> Exposure to specialist care is associated with incremental reductions in the hazard of premature mortality. Those referred to a comprehensive epilepsy program received the greatest benefit.
Parent-Based Interventions to Affect Adolescent Sexual and Reproductive Health
Authors: Vincent Guilamo-Ramos, Adam Benzekri, Marco Thimm-Kaiser
Journal: JAMA Pediatrics (2019)

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Lung Cancer in Nonelderly Patients: Facility and Patient Characteristics Associated With Not Receiving Treatment
Authors: Elizabeth A. Nardi, Can-Lan Sun, Francisco Robert, Julie A. Wolfson
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: In elderly patients with lung cancer, race/ethnicity is associated with not receiving treatment; however, little attention has been given to nonelderly patients (aged ≤65 years) with a range of disease stages and histologies. Nonelderly patients with lung cancer have superior survival at NCI-designated Comprehensive Cancer Centers (CCCs), although the reasons remain unknown. Patients and Methods: A retrospective cohort study was conducted in 9,877 patients newly diagnosed with small cell or non–small cell lung cancer (all stages) between ages 22 and 65 years and reported to the Los Angeles County Cancer Surveillance Program registry between 1998 and 2008. Multivariable logistic regression examined factors associated with nontreatment. Results: In multivariable analysis, race/ethnicity was associated with not receiving cancer treatment (black: odds ratio [OR], 1.22; P =.004; Hispanic: OR, 1.17; P =.04), adjusting for patient age, sex, disease stage, histology, diagnosis year, distance to treatment facility, type of facility (CCC vs non-CCC), and insurance status. With inclusion of socioeconomic status (SES) in the model, the effect of race/ethnicity was no longer significant (black: OR, 1.02; P =.80; Hispanic: OR, 1.00; P =1.00). Factors independently associated with nontreatment included low SES (OR range, 1.37–2.15; P &lt;.001), lack of private insurance (public: OR, 1.71; P &lt;.001; uninsured: OR, 1.30; P &lt;.001), and treatment facility (non-CCC: OR, 3.22; P &lt;.001). Conclusions: In nonelderly patients with lung cancer, SES was associated with nontreatment, mitigating the effect of race/ethnicity. Patients were also at higher odds of nontreatment if they did not have private insurance or received cancer care at a non-CCC facility. These findings highlight the importance of understanding how both patient-level factors (eg, SES, insurance status) and facility-level factors (eg, treatment facility) serve as barriers to treatment of nonelderly patients with lung cancer.