tbuckley/cabot-search huggingface dataset:
Tumor protein expression of BRCA1 and development of lethal prostate cancer.
Authors: Carl Ceraolo, Travis A. Gerke, Piotr Zareba, Andreas Pettersson, Konrad H. Stopsack, Dipanjan Chowdhury, Ericka M. Ebot, Richard Flavin, Stephen P. Finn, Philip W. Kantoff, Meir J. Stampfer, Massimo Loda, Michelangelo Fiorentino, Lorelei A. Mucci
Journal: Journal of Clinical Oncology (2020)

65 Background: DNA repair genes including BRCA1 are commonly altered in metastatic prostate tumors. However, mutations and copy number aberrations in these genes are rare in primary tumors. Instead, preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. Methods: We undertook a prospective study of tumor BRCA1 protein expression and lethal prostate cancer among men with clinically localized prostate cancer in the Health Professionals Follow-up Study. We performed immunohistochemical staining for BRCA1 on tumor tissue microarrays using a validated antibody and scored expression as positive or negative. We also assessed tumor proliferation by immunostaining for Ki67, angiogenesis by immunostaining for CD34, and apoptosis using a TUNEL assay. Proportional hazards regression was used to evaluate the association between BRCA1 protein expression and development of lethal prostate cancer (metastasis or cancer-specific death). Results: Ten percent of tumors (60 of 589) stained positive for the BRCA1 protein. BRCA1-positive tumors were characterized by higher Gleason scores, a higher proliferative index, and a higher apoptotic index. During a median follow-up of 14.3 years, 18 men (34%) in the BRCA1-positive group and 74 men (14%) in the BRCA1-negative group developed lethal prostate cancer. There was a strong positive association between BRCA1 protein expression and lethal prostate cancer in both unadjusted analyses (HR 2.71, 95% CI 1.73–4.26) and after adjusting for clinical factors (HR 2.00, 95% CI 1.26–3.18). The positive association with BRCA1 protein expression was also independent of proliferation index. Conclusions: Primary prostate tumors expressing the BRCA1 protein have a highly proliferative phenotype and are more likely to progress to lethal disease, independent of its higher proliferative index. Assessing tumor protein expression of BRCA1 may help elucidate the Janus-faced role of DNA repair pathways in prostate cancer progression.[Table: see text]
Optimal timing of radical cystectomy after neoadjuvant chemotherapy in muscle invasive bladder cancer (MIBC).
Authors: Saurabh Parasramka, Janeesh Sekkath Veedu, Quan Chen, Bin Huang, Peng Wang, Zin Myint
Journal: Journal of Clinical Oncology (2020)

509 Background: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) with bilateral pelvic lymph node dissection is the current standard of care for MIBC. Pathologic downstaging with NAC is an important surrogate endpoint and associated with overall survival benefit. There have been questions about the impact of delay in definitive surgery because of NAC. The optimal timing of surgery from the start of NAC is uncertain. We studied this question using National Cancer Database (2004-2015). Methods: We identified patients with MIBC (cT2-T4aN0M0 &amp; cT1-T4aN1M0) who received NAC within 6 months of diagnosis and underwent surgery between 10 weeks and 9 months of the start day of NAC. We excluded patients who died within 30 days of surgery. Time period was stratified into three cohorts; 11-16, 17-24, and ≥25 weeks from the start day of NAC. Descriptive analysis, Kaplan-Meier plots, Log-Rank tests for univariate and proportional hazards models for multivariate survival analyses were performed. Results: 3709 patients were identified; 75% were males, 77% cases were cT2 and 73% had charlson-deyo score (CS) of '0'. Median time for surgery 10 weeks after start of NAC was 118 days. Forty-two (42%) had surgery in 11-16, 47% in 17-24 and 9.9% in ≥25 weeks. Majority (60%) were treated at academic and 24% at comprehensive community. Only 29% achieved complete pathological complete response rate (Tis or T0). On univariate analysis receiving NAC within 3 months of diagnosis was significantly associated with survival benefit (p &lt; 0.001). Cox-regression results showed that patients who underwent surgery in 11-16 and 17-24 week time period had significantly better survival than &gt; 25 week group with HR of 0.84 (0.71- 0.98) and 0.82 (0.70-0.97) respectively. In addition patients with CS of '0' had better survival with HR 0.78 (0.62-0.90) and &gt; 75 years of age was associated with worse survival HR 1.73 (1.35-2.22). Conclusions: Our study indicates that appropriate patients with MIBC benefit from receiving surgery within 24 weeks of starting NAC. However, randomized prospective study is warranted to further explore the role of delay of surgery from NAC.
Association of an immune gene signature with pathologic response and outcome after neoadjuvant pembrolizumab (pembro), compared to neoadjuvant chemotherapy (NAC), in muscle-invasive bladder cancer (MIBC).
Authors: Andrea Necchi, Daniele Raggi, Alberto Briganti, Elena Farè, Patrizia Giannatempo, Laura Marandino, Marco Bianchi, Andrea Gallina, Andrea Salonia, Giorgio Gandaglia, Nicola Fossati, Umberto Capitanio, Francesco Montorsi, Joost L. Boormans, Yang Liu, Joep de Jong, Peter C. Black, Ryan Dittamore, Elai Davicioni, Ewan Gibb
Journal: Journal of Clinical Oncology (2020)

533 Background: In the PURE01 study (NCT02736266), neoadjuvant pembro resulted in 42% pathologic complete responses (pT0) in patients (pts) with MIBC. In this study, we investigated immune transcriptome signatures and molecular subtyping as potential predictors of pembro efficacy. Methods: Pts enrolled in the PURE01, which is still recruiting pts in its amended design, had predominant urothelial carcinoma histology and stage cT≤4N0 MIBC. Biomarker analyses included transcriptome profiling for 78 pts. A cisplatin-based NAC cohort of 140 cT≤4N0 MIBC pts was used for comparison. The association of Immune190, immune hallmark RNA signatures and molecular subtypes (TCGA, Consensus classifier, Genomic subtyping classifier [GSC]) was evaluated with respect to pT0 and recurrence-free survival (RFS). Multivariable logistic regression analyses (MVA) were used adjusting for the clinical T-stage and gender. Results: The Immune190 signature was significant for pT0 on MVA (OR: 1.54, 95%CI: 1.1-2.3, p=0.02) in the PURE01 cohort, but not in NAC cohort (OR: 0.96, 95%CI: 0.8-1.2, p=0.73). The hallmarks for IFN-γ (OR: 1.10, 95%CI: 1-1.2, p=0.007) and IFN-α response (OR: 1.07, 95%CI: 1-1.1, p=0.009) were also associated with pT0 for PURE01, but not for NAC (IFN-γ: OR: 0.99, 95%CI: 0.9-1.1, p=0.846 and INF-α: OR: 0.99, 95%CI: 0.95-1.04, p=0.806). In PURE-01, patients with Immune190 scores &gt;0.35 had 100% 2-y RFS vs 80% of those with ≤0.35; no difference was observed in NAC pts, as well as for the other hallmarks in both groups. The neuroendocrine (NE)-like subtype had the worst 2-y RFS in all three subtyping models (33%, p&lt;0.01) whereas the GSC Claudin-low subtype had the best outcome with no recurrences within 24 months. The other subtypes had RFS ranging from 75-86% in TCGA, 53-89% in Consensus, and 74-92% in the GSC. Conclusions: We found RNA Immune190 signature was reliably associated with response and outcome after neoadjuvant pembro. Molecular subtyping revealed special subtypes with outlier outcomes. These data suggest RNA profiling may provide a potential tool for personalizing the neoadjuvant therapy approach. Clinical trial information: NCT02736266.
Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates <i>MYCN</i> -amplified neuroblastoma growth
Authors: Yu-Feng Guo, Jiang-Jie Duan, Jun Wang, Lin Li, Di Wang, Xun-Zhou Liu, Jing Yang, Hua-Rong Zhang, Jing Lv, Yong-Jun Yang, Ze-Yu Yang, Jiao Cai, Xue-Mei Liao, Tao Tang, Ting-Ting Huang, Feng Wu, Xian-Yan Yang, Qian Wen, Xiu-Wu Bian, Shi-Cang Yu
Journal: Science Translational Medicine (2020)

The ALDH18A1-MYCN positive feedback loop points to a promising therapeutic target in MYCN -amplified neuroblastoma.
Targeting birch allergy with monoclonal IgG antibodies that bind allergen and prevent IgE effector cell activation
Authors: Amanda Atanasio, Matthew Franklin, Li-Hong Ben, Ashok Badithe, Joannie Bautista, Vishal Kamat, Annabel Romero Hernandez, William Olson, Andrew Murphy, matthew sleeman, Jamie Orengo
Journal: Journal of Allergy and Clinical Immunology (2020)
Accelerating the development of novel technologies and tools for the subcutaneous delivery of biotherapeutics
Authors: David S. Collins, Manuel Sánchez-Félix, Advait V. Badkar, Randall Mrsny
Journal: Journal of Controlled Release (2020)

Subcutaneous (SC) delivery of biotherapeutics is well established as a route of administration across many therapeutic areas and has been shown to be effective and well-tolerated. It can offer several advantages over intravenous administration. This notwithstanding, there remain critical development issues and knowledge gaps in SC drug delivery. To articulate and address these issues, the SC Drug Delivery and Development Consortium was convened in 2018 as a pre-competitive collaboration of industry experts in drug delivery, device development, and commercialization. In this review, we outline the Consortium's vision and mission in advancing the development of patient-centered biotherapeutics and establishing a collaborative organization that facilitates open sharing of information and gives voice to diverse viewpoints from SC experts across industries and disciplines. Additionally, we describe the current landscape and challenges associated with SC administration of therapeutic proteins (specifically monoclonal antibodies) and offer insights into potential solutions to these challenges within the context of 8 problem statements developed by the Consortium to highlight key gaps, unmet needs, and actionable issues. Current and future opportunities to accelerate progress in the field through technological advances and the development of drug delivery tools are also discussed.
Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis
Authors: Maria Inês Cunha, Minhui Su, Ludovico Cantuti-Castelvetri, Stephan A. Müller, Martina Schifferer, Minou Djannatian, Ioannis Alexopoulos, Franziska van der Meer, Anne Winkler, Tjakko J. van Ham, Bettina Schmid, Stefan F. Lichtenthaler, Christine Stadelmann, Mikael Simons
Journal: The Journal of Experimental Medicine (2020)

Remyelination requires innate immune system function, but how exactly microglia and macrophages clear myelin debris after injury and tailor a specific regenerative response is unclear. Here, we asked whether pro-inflammatory microglial/macrophage activation is required for this process. We established a novel toxin-based spinal cord model of de- and remyelination in zebrafish and showed that pro-inflammatory NF-κB–dependent activation in phagocytes occurs rapidly after myelin injury. We found that the pro-inflammatory response depends on myeloid differentiation primary response 88 (MyD88). MyD88-deficient mice and zebrafish were not only impaired in the degradation of myelin debris, but also in initiating the generation of new oligodendrocytes for myelin repair. We identified reduced generation of TNF-α in lesions of MyD88-deficient animals, a pro-inflammatory molecule that was able to induce the generation of new premyelinating oligodendrocytes. Our study shows that pro-inflammatory phagocytic signaling is required for myelin debris degradation, for inflammation resolution, and for initiating the generation of new oligodendrocytes.
Hospital-level quality indicators for kidney cancer surgery: A Veteran’s Affairs national health system validation of concept.
Authors: Diego Aguilar Palacios, Brigid Wilson, Olli Saarela, Mustafa Ascha, Sunah Song, Molly Elmer DeWitt-Foy, Keith Lawson, Jill Barnholtz-Sloan, Antonio Finelli, Steven Campbell, Robert Abouassaly
Journal: Journal of Clinical Oncology (2020)

667 Background: Validation and implementation of quality indicators (QIs) for oncological surgical care is imperative in national health care systems. However, QIs must be adjusted for significant case-mix variations among hospitals and to capture disparate patient outcomes. Here, we explore and validate a compound quality score (CQS) as a metric for hospital-level quality of care in kidney cancer patients. Methods: Kidney cancer patients (n = 8233) treated at the VA (2005-2015) were identified. Two previously described and validated process QIs were explored: the proportion of patients with a) T1a tumors undergoing partial nephrectomy; and b) T1-T2 tumors undergoing minimally invasive radical nephrectomy. Demographics, comorbidity, tumor characteristics and treatment year were used for case-mix adjustment using indirect standardization / multivariable regression models. The predicted vs observed ratio of cases was calculated to generate each QI score. CQS represents the sum of both QIs scores. Ninety-six hospitals were benchmarked by CQS and patient-level outcomes were regressed on CQS levels to assess for length of stay (LOS), 30 days complications/readmission, 90 days overall mortality and total cost of surgical admission. Results: CQS identified 25, 33 and 38 hospitals with higher, lower and average performance, respectively. Total CQS score was independently associated with LOS [β = -0.04, p&lt; 0.01, predicted LOS 0.84 days shorter for CQS = 2 vs. CQS = -2], 30 days surgical complications [OR = 0.88, p &lt; 0.01] or 30 days medical complications [OR = 0.93, p &lt; 0.01] and total cost of surgical admission [β = -0.014, p&lt; 0.01, predicted 12% lower cost for CQS = 2 vs. CQS = -2]. No association was found between CQS and 30 day readmissions or 90 days mortality (all p&gt;0.05), although low event rates were observed (8.9% and 1.7%, respectively). Conclusions : Variability in quality of surgical care at a hospital-level can be captured with the CQS among kidney cancer patients. CQS is associated with length of stay, post-operative complications and total cost of surgical admission. Quality indicators should be used to identify, audit and implement quality improvement strategies across health systems.
Predicting long-term results with circulating tumor cells in patients with de novo androgen sensitive prostate cancer treated with hTERT peptides vaccine.
Authors: Wolfgang Lilleby, Ingrid Jenny Guldvik, Knut H. Hole, Richard Olaussen, Ian G. Mills, Andreas Stensvold, Therese Seierstad, Phuoc T. Tran, Else Marit Inderberg
Journal: Journal of Clinical Oncology (2020)

98 Background: Androgen deprivation, radiotherapy and chemotherapy improves survival in advanced prostate cancer (PC), but many patients still progress and experience toxicity from treatment. We investigated the clinical utility of a medical wire, collecting circulating tumor cells (CTCs) from a peripheral vein, to predict oncologic outcomes prior to treatment with a hTERT peptide vaccine. Methods: Twenty-three patients with advanced PC with non-visceral spread and unselected HLA-type were eligible. One patient progressed before initiation of the vaccination (median FU 60 months). The hTERT peptides vaccine schedule started one week after inclusion with a total of 13 vaccinations (N=22). Patients with no signs of deterioration during the vaccine schedule received image-guided radiation to the prostate (2Gy/37f, n=20). Vaccine response was evaluated by T-cell proliferation assay. CTCs were enriched from the peripheral blood using EpCAM as antibody (CellCollector, Gilupi, Potsdam, Germany). Kaplan-Meier outcome curves were constructed for prostate cancer-specific survival (PCSS) and overall survival with stratification by immune response, CTCs (no/yes), PSA and comparison of patient subsets using the log-rank test. Results: Median age of the cohort was 67 years (range 51-78 years).The mean time from CellCollector after ADT to start vaccine was 2,95 months (SD+-1,78 months). The mean yield of CTCs was 3 cells (range 0 - 22). The detection of CTCs showed an inverse trend towards immune response (p=0.07). None of the patients with a positive CellCollector finding and a PSA below ≤0.2 (n=9) had died of prostate cancer during the observation period of 5 years, patients with no CTCS and a PSA &gt;0.2 (n=14) had an estimated median PCSS of 39 months (log-rank test 0=0.007, Fig. 1). The overall survival analysis showed that 6 out of 9 patients with CTCs compared to 5 out of 14 patients in the CTCs negative group were alive at 5 years FU (log-rank-test=0.159). Conclusions: Patients with a de novo diagnozed metastatic prostate cancer and a positive CTC burden do better when subsequently treated with the hTERT vaccine than those with a negative CTC finding. Clinical trial information: NCT01784913.
Intratumoral Immunotherapy for Early-stage Solid Tumors
Authors: Wan Xing Hong, Sarah Haebe, Andrew S. Lee, C. Benedikt Westphalen, Jeffrey A. Norton, Wen Jiang, Ronald Levy
Journal: Clinical Cancer Research (2020)

Abstract The unprecedented benefits of immunotherapy in advanced malignancies have resulted in increased interests in exploiting immune stimulatory agents in earlier-stage solid tumors in the neoadjuvant setting. However, systemic delivery of immunotherapies may cause severe immune-related side-effects and hamper the development of combination treatments. Intratumoral delivery of neoadjuvant immunotherapy provides a promising strategy in harnessing the power of immunotherapy while minimizing off-target toxicities. The direct injection of immune stimulating agents into the tumor primes the local tumor-specific immunity to generate a systemic, durable clinical response. Intratumoral immunotherapy is a highly active area of investigation resulting in a plethora of agents, for example, immune receptor agonists, non-oncolytic and oncolytic viral therapies, being tested in preclinical and clinical settings. Currently, more than 20 neoadjuvant clinical trials exploring distinct intratumoral immune stimulatory agents and their combinations are ongoing. Practical considerations, including appropriate timing and optimal local delivery of immune stimulatory agents play an important role in safety and efficacy of this approach. Here, we discuss promising approaches in drug delivery technologies and opportunity for combining intratumoral immunotherapy with other cancer treatments and summarize the recent preclinical and clinical evidences that highlighted its promise as a part of routine oncologic care.
Self-assembled colloidal gold superparticles to enhance the sensitivity of lateral flow immunoassays with sandwich format
Authors: Xirui Chen, Yuankui Leng, Liangwen Hao, Hong Duan, Jing Yuan, Wenjing Zhang, Xiaolin Huang, Yonghua Xiong
Journal: Theranostics (2020)

Background: Traditional lateral flow immunoassay (LFIA) based on 20-40 nm gold nanoparticles (AuNPs) as signal reporter always suffers from relatively low detection sensitivity due to its insufficient brightness, severely restricting its wide-ranging application in the detection of target analytes with trace concentration. Methods: To address this problem, the self-assembled colloidal gold superparticles (GSPs) were synthesized as an improved absorption-dominated labeling probe for improving the sensitivity of sandwich LFIA. Five kinds of GSPs with the size ranging from 100 nm to 400 nm were synthesized by embedding hydrophobic AuNPs of size 12 nm as building blocks into the polymer nanobeads. The as-prepared GSPs were suggested as novel labeling probes of LFIA. The effects of the size of assembled GSPs on the sensitivity of sandwich LFIA was assessed, and the detection performance of GSPs-LFIA was further compared with traditional AuNPs-LFIA. Results: The resultant GSPs showed extremely high light absorption but very low light scattering, which favor the absorption-dominated signal output in LFIA. Among them, the GSP270-LFIA (size 270 nm) exhibits the highest sensitivity for human chorionic gonadotropin and hepatitis B surface antigen detection in real serum sample, which are approximate 39.79- and 13.8-fold higher than that of traditional AuNP40-LFIA. Conclusions: The proposed research demonstrated that the current GSPs can provide an ultrasensitive and quantitative detection for disease biomarkers in real serum samples as promising reporters of sandwich LFIA platform.
Adjuvant radiotherapy following radical prostatectomy for prostate cancer: A systematic review and meta-analysis.
Authors: Tobias Engel Ayer Botrel, Otávio Clark, Francisco Flávio Horta Bretas, Marcus V. Sadi, Ubirajara Ferreira, Luciano Paladini, Wagner Eduardo Matheus, Rodolfo Reis, Ronilson Oliveira Duraes, Antônio Carlos Lima Pompeu
Journal: Journal of Clinical Oncology (2020)

366 Background: To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing efficacy of adjuvant radiotherapy (AR) versus expectant management (EM) in men who undergo radical prostatectomy for localized prostate cancer (CaP). Methods: To perform this review and meta-analysis,several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. We included all the studies that compared AR versus EM after radical surgery for CaP. The primary endpoints analyzed were biochemical progression-free survival (bPFS), metastasis-free survival (MPFS), prostate cancer-specific survival (CSS), overall survival (OS) and side effects. The data extracted from the studies were combined by using the Hazard Ratio (HR) or Risk Ratio (RR) with their corresponding Confidence Intervals of 95% (CI95%). Results: Overall, 68 studies were identified and screened. The final analysis included 7 trials (EORTC 22911, SWOG 8794, ARO 96-02/AUO AP 09/95, RAVES, FINNISH, GETUG-AFU 17 and RADICALS-RT) comprising 4,221 patients. The bPFS was higher in patients who received AR (fixed effect: HR = 0.58, CI95% = 0.52 to 0.66; p &lt; 0.00001) but with significant heterogeneity (Chi 2 = 40.34, df = 6 (P &lt; 0.00001); I 2 = 85%). We performed a random-effect model analysis to better explore this heterogeneity: in this analysis, the result remained in favor of AR (random effect: HR = 0.64, CI95% = 0.45 to 0.90; p = 0.01). The MPFS also was higher in patients who received AR (HR = 0.77, CI95% = 0.65 to 0.91; p = 0.002). The CSS and OS were not statistically different in patients with or without adjuvant radiotherapy (HR = 0.79, CI95% = 0.47 to 1.32; p = 0.36 and HR = 0.92, CI95% = 0.77 to 1.11; p = 0.38, respectively). The incidence of adverse events (gastrointestinal and genitourinary) were higher in the AR group. Conclusions: This is the first meta-analysis including the seven available RCTs in the literature (the previous meta-analysis reviewed only three), comparing adjuvant radiotherapy versus expectant management following radical prostatectomy for CaP. Adjuvant radiotherapy statistically increased the bPFS and MPFS, but did not have an impact on the OS or CSS.
Response by Lüker et al to Letter Regarding Article, “Internal Versus External Electrical Cardioversion of Atrial Arrhythmia in Patients With Implantable Cardioverter-Defibrillator: A Randomized Clinical Trial”
Authors: Jakob Lüker, Kathrin Kuhr, Arian Sultan, Georg Nölker, Hazem Omran, Stephan Willems, René Andrié, Jan W. Schrickel, Stefan Winter, Dirk Vollmann, Roland R. Tilz, Alexander Jobs, Christian-H. Heeger, Andreas Metzner, Sven Meyer, Karl Mischke, Andreas Napp, Andreas Fahrig, Susanne Steinhauser, Johannes Brachmann, Stephan Baldus, Rajiv Mahajan, Prashanthan Sanders, Daniel Steven
Journal: Circulation (2020)