tbuckley/cabot-search huggingface dataset:
Impact of PSMA PET/CT on SRT planning: Preliminary results from the randomized phase III trial NCT03582774.
Authors: Jeremie Calais, Wesley R Armstrong, Amar Upadhyaya Kishan, Kiara M Booker, David Elashoff, Wolfgang Peter Fendler, Johannes Czernin, Nicholas George Nickols
Journal: Journal of Clinical Oncology (2021)

30 Background: The purpose of this trial is to evaluate the success rate of salvage radiation therapy (SRT) for recurrence of prostate cancer (PCa) after radical prostatectomy with and without planning based on prostate specific membrane antigen (PSMA) positron emission tomography (PET). Methods: This is a multicenter, prospective, randomized, controlled, open-label, Phase 3 clinical imaging trial powered for clinical outcome at 5 years. UCLA is the leading central site in which PSMA PET, clinical follow-up and data management are being done. UCSF was a participating site in which PSMA PET imaging can be done. SRT can be performed anywhere, patients are followed remotely by the UCLA investigators. Patients scheduled for SRT for recurrence after primary prostatectomy and with PSA ≥ 0.1ng/ml at time of enrollment were eligible. Patients were randomized to proceed with standard SRT allowing for any conventional imaging aside from PSMA PET/CT (control arm) or undergo a 68Ga-PSMA-11 PET/CT scan prior to SRT planning (investigational arm). The primary endpoint is the success rate of SRT at 5 years in patients who undergo SRT. We report here the preliminary results of a secondary endpoint: the impact of PSMA PET on SRT planning by comparing the pre-randomization RT plans prospectively obtained on surveys before randomization to the actually delivered RT plans obtained after follow-up. Results: Enrollment of the trial was complete. 193 patients were enrolled from 09.06.2018 to 08.17.2020. 7/90 patients (9%) in the control arm dropped-out the study because they underwent a PSMA PET at another institution, while 1/103 (1%) patients of the intervention arm dropped-out due to COVID-19 related complications. After a median follow-up of 13.3 months (last follow-up date 09/01/2020), delivered RT plans were obtained in 60/83 (72%) and 70/102 (69%) of patients of the control and the PSMA arms, respectively. Median PSA at enrollment was 0.32 ng/ml (IQR 0.17-1.35) and 0.22 ng/ml (IQR 0.14-0.50) in the control and PSMA arms, respectively. There was a change between the intended pre-randomization RT plan and the actually delivered RT plan in 17/60 (28%) and 40/70 (57%) of the patients in the control and PSMA arms, respectively (p = 0.002). SRT was aborted in favor of systemic therapy and/or metastasis directed RT for extra-pelvic M1 disease in 2/60 (3%) and 12/70 (17%) of the control and PSMA arms, respectively (p = 0.17). Dose prescription and/or target volume delineation was changed in 2/60 (3%) and 1/70 (26%) in the control and PSMA arms, respectively (p = 0.001). Conclusions: In this prospective randomized phase 3 study, PSMA PET had an impact on the SRT plan in more than half of the patients. Long-term follow-up will show if the impact of PSMA PET on SRT planning translates into improved outcome or not. Clinical trial information: NCT03582774.
In adults, the Oxford/AstraZeneca vaccine had 70% efficacy against COVID-19 &gt;14 d after the 2nd dose
Authors: Zain Chagla
Journal: Annals of Internal Medicine (2021)

Voysey M, Clemens SA, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021;397:99-111. 33306989.
Abstract 15269: Real World Analysis of Efficacy of Remote Pulmonary Artery Hemodynamic Monitoring in Female and Male Population
Authors: Smitha Narayana Gowda, Udit B Bhatnagar, Adam Stys, Tom Stys, Marian S Petrasko, Naveen Rajpurohit, Valerie Bares, Orvar Jonsson
Journal: Circulation (2019)

Introduction: Remote pulmonary artery (PA) hemodynamic monitoring device has shown to decrease heart failure (HF) related readmissions. However, in literature there have been concerns about the eff...
Reply to Mulla and Pathak: Sleep Apnea and Poor COVID-19 Outcomes: Beware of Causal Intermediates and Colliders
Authors: Brian E. Cade, Hassan S. Dashti, Syed M. Hassan, Susan Redline, Elizabeth W. Karlson
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

DAG (5).In Figure 2 (again, representing an association that may be studied in a hypothetical study), hypertension is a collider on the path from OSA to PO. Variable U in Figure 2 is an unmeasured variable, such as a medication or illness, that affects the risk of both hypertension and PO.If the data analyst controls for hypertension but does not control for U in this situation, then collider stratification bias will occur (3, 6).Controlling for a collider can result in a bias that is strong enough to move the observed association in a direction that is opposite of the true effect (3).Interestingly, in the analysis by Cade and colleagues, the odds ratio for the outcome of inpatient admission moved from 1.55 in the unadjusted model to 0.91 in model 4 (1).Without additional information, we cannot offer a reason why the odds ratio shifted to the other side of the null value of 1 in Cade's study.DAGs are useful tools for identifying the minimally sufficient set of variables to control for to reduce confounding bias (3).Investigators may disagree over which DAG is correct for any given possible association.The DAGs presented here are overly simplistic.
The systemic treatment of recurrent ovarian cancer revisited
Authors: T. Baert, A. Ferrero, J. Sehouli, D.M. O'Donnell, A. González-Martín, F. Joly, J. van der Velden, P. Blecharz, D.S.P. Tan, D. Querleu, N. Colombo, A. du Bois, J.A. Ledermann
Journal: Annals of Oncology (2021)
43P Pre-clinical evaluation of potent and orally bioavailable next-generation inhibitors targeting the family of mutants that drive oncogenic BRAF dimer formation
Authors: Y-C. Han, P.Y. Ng, R. Schulz, S.N. Yang, A. Lelo, L.S. Ogawa, M. O'Connor, N. Ishiyama, I. Jewett, D. Romashko, A. Salomatov, S. Thakur, S. Smith, E. Buck, C. Roberts, M. Lucas, T-A. Lin
Journal: Annals of Oncology (2021)
MACMIC Reveals a Dual Role of CTCF in Epigenetic Regulation of Cell Identity Genes
Authors: Guangyu Wang, Bo Xia, Man Zhou, Jie Lv, Dongyu Zhao, Yanqiang Li, Yiwen Bu, Xin Wang, John P. Cooke, Qi Cao, Min Gyu Lee, Lili Zhang, Kaifu Chen
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Numerous studies of relationship between epigenomic features have focused on their strong correlation across the genome, likely because such relationship can be easily identified by many established methods for correlation analysis. However, two features with little correlation may still colocalize at many genomic sites to implement important functions. There is no bioinformatic tool for researchers to specifically identify such feature pairs. Here, we develop a method to identify feature pairs in which two features have maximal colocalization minimal correlation (MACMIC) across the genome. By MACMIC analysis of 3306 feature pairs in 16 human cell types, we reveal a dual role of CCCTC-binding factor (CTCF) in epigenetic regulation of cell identity genes. Although super-enhancers are associated with activation of target genes, only a subset of super-enhancers colocalized with CTCF regulate cell identity genes. At super-enhancers colocalized with CTCF, CTCF is required for the active marker H3K27ac in cell types requiring the activation, and also required for the repressive marker H3K27me3 in other cell types requiring repression. Our work demonstrates the biological utility of the MACMIC analysis and reveals a key role for CTCF in epigenetic regulation of cell identity. The code for MACMIC is available at https://github.com/bxia888/MACMIC.
Characteristics of p.Gln368Ter Myocilin Variant and Influence of Polygenic Risk on Glaucoma Penetrance in the UK Biobank
Authors: Nazlee Zebardast, Sayuri Sekimitsu, Jiali Wang, Tobias Elze, Puya Gharahkhani, Brian S. Cole, Michael M. Lin, Ayellet V. Segrè, Janey L. Wiggs, Tin Aung, Jamie E. Craig, Ching-Yu Cheng, Jessica N. Cooke Bailey, Angela J. Cree, Paul J. Foster, Puya Gharahkhani, Christopher J. Hammond, Alex W. Hewitt, René Höhn, Pirro G. Hysi, Adriana I. Iglesias, Jost B. Jonas, Caroline C.W. Klaver, Anthony P. Khawaja, Chiea Chuen Khor, Andrew J. Lotery, Stuart MacGregor, David A. Mackey, Jue Sheng Ong, Paul Mitchell, Louis R. Pasquale, ChiPui Pang, Francesca Pasutto, Norbert Pfeiffer, Ayellet V. Segre, Cornelia M. van Duijn, Ananth C. Viswanathan, Veronique Vitart, Eranga N. Vithana, Janey L. Wiggs, Robert Wojciechowski, Terri L. Young, Tien Yin Wong, Seyhan Yazar
Journal: Ophthalmology (2021)
Normal tissue complication probabilities (NTCP) of urethral stricture following salvage SBRT or HDR for periurethral recurrences following prior definitive radiation therapy.
Authors: Russell Injerd, Kristen Burnham, Matthew Walb, Bruce Hershatter, Sagar A Patel, Benjamin Walker Fischer-Valuck
Journal: Journal of Clinical Oncology (2021)

246 Background: SBRT and HDR brachytherapy have emerged as definitive salvage re-irradiation options for men with locally recurrent prostate cancer after prior radiation therapy (RT). Toxicity with re-irradiation remains a concern in this setting, particularly for salvage of periurethral recurrences. We calculated the normal tissue complication probability (NTCP) of urethral stricture following salvage re-irradiation (HDR and SBRT) after previous definitive RT (external beam or HDR) for periurethral recurrences. Methods: Two upfront definitive treatment plans were generated for 5 men with localized prostate cancer: External Beam RT (EBRT 1 ) to a dose of 79.2 Gy in 1.8 Gy fractions and HDR monotherapy (HDR 1 ), 13.5 Gy x 2 implants. Periurethral recurrences were virtually created on diagnostic MRI scans for each of the five men and defined as a recurrent dominant intraprostatic lesion (DIL). Three salvage RT plans were generated for each patient (constraints in Table): HDR salvage (10 Gy whole gland; 13.5 Gy to DIL; 2 implants), SBRT r with maximal rectal sparing (constraints designed for salvage following prior EBRT; 30 Gy in 5 fractions whole gland; 40 Gy in 5 fractions to DIL), and SBRT u with maximal urethral sparing (constraints designed for patients with prior HDR monotherapy; same Rx). DVH data was collected for each plan (previous RT and each salvage approach) and the equivalent uniform dose (EUD) was calculated. NTCP for the urethral stricture in the summed plans (prior definitive treatment + each salvage plan) was calculated by the Lyman-Kutcher-Burman model using the following parameters: (α/β = 5Gy; TD 50 = 116.7; m = 0.23; n = 0.3). Results: Prescription coverage of 90% of the DIL volume was achieved for each plan. The mean NTCP of urethral stricture for EBRT 1 + HDR salvage was 55.2% (range, 52.2-59.1%) and for HDR 1 + HDR salvage was 49.2% (42.9-57.5%). For EBRT 1 + SBRT r and EBRT 1 + SBRT u the NTCP for urethral stricture was 54.0% (50.4-61.0%) and 43.2% (39.4-48.4%), respectively. The NTCP of urethral stricture for HDR 1 + SBRT r was 48.1% (41.0-57.2%) and for HDR 1 + SBRT u was 37.6% (30.9-44.6%). Conclusions: In this modeling analysis of salvage RT for periurethral recurrences following previous RT (EBRT or HDR monotherapy), the NTCP for urethral stricture was numerically lowest for salvage SBRT using maximum urethral sparing dose constraints in comparison to salvage SBRT with maximum rectal sparing constraints or salvage HDR brachytherapy. This type of analysis lends insight into personalized treatment planning based on previous RT modality and previous dose to organs at risk. Expanded analysis is underway. [Table: see text]
Over-the-scope clipping and detachable snare ligation as a novel combination hemostatic therapy for diverticular bleeding
Authors: Koichiro Kawano, Reiko Kawano, Tomonori Moriguchi, Hiroshi Tanabe, Takao Katoh, Katsuhisa Nishi, Mamoru Takenaka
Journal: Endoscopy (2021)

Ligation therapy, such as endoscopic band ligation and detachable snare ligation, is an effective treatment for colonic diverticular hemorrhage [1] [2]. However, delayed perforation has been reported in patients undergoing steroid therapy and endoscopic ligation [3]. As an alternative, over-the-scope (OTS) clipping enables full-thickness resection at the central tissue mound of the inverted diverticulum while preventing perforation ([Fig. 1]) [4]. Recent reports have described that OTS clipping is effective for hemostasis of diverticular bleeding; however, early rebleeding was observed in 33 % of patients treated with OTS clips alone ([Fig. 2 a], [Fig. 3]) [5].
Pegylated liposomal doxorubicin-induced hand-foot syndrome predicted by serum metabolomic profiling and prevented by calcium dobesilate
Authors: Zhenchuan Song, Fuguo Tian, Shuo Feng, Lingzi Shi, Xiaoqing Chen, Xiaohan Liu, Meiqi Wang, Yixin Qi, Tianli Hui, Yuming Fu
Journal: Journal of the American Academy of Dermatology (2021)
Bladder tumor metabolic alterations in response to IFNα gene therapy.
Authors: Tanner Miest, Anirban P Mitra, Vikram M Narayan, Colin P.N. Dinney, Sharada Mokkapati
Journal: Journal of Clinical Oncology (2021)

468 Background: Intravesical interferon-alpha (IFNα) gene therapy with Nadofaragene firadenovec has shown clinical efficacy in patients with non-muscle invasive bladder cancer (NMIBC) in a phase III clinical trial, highlighting the therapeutic potential of this approach in a disease with significant unmet clinical need. Optimizing the clinical efficacy of IFNα gene therapy requires an understanding of the underlying therapeutic mechanisms. Here, we investigate the impact of IFNα gene therapy on tumor metabolism using in vitro and orthotopic murine preclinical models and clinical trial data to elucidate mechanisms of tumor resistance and identify predictive biomarkers. Methods: In vitro murine bladder cancer cell lines treated with recombinant IFNα (rIFNα) and lentiviral IFNα (LV-IFNα) were analyzed by whole-transcriptome sequencing, glucose uptake, and lactate production. Preclinical murine bladder cancer models were treated with LV-IFNα (orthotopic tumor model) or Poly(I:C) (flank tumor model), a potent IFN inducer. Disease response was monitored by in vivo real-time luciferase imaging. Tumors were harvested and whole-transcriptome sequencing performed to assess effects of IFNα therapy on tumor metabolism and lipidomics. Lipidomic profiling was performed on patient urine samples from a phase II clinical trial of intravesical Nadofaragene firadenovec (7 clinical responders and 6 non-responders) to assess for clinically-relevant differences in lipid metabolism. Results: Following IFNα therapy in vitro and in murine orthotopic bladder cancer models, we identified downregulation of genes involved in fatty acid synthesis and upregulation of genes involved in glycolysis by whole-transcriptome sequencing. This was confirmed by higher glucose uptake and lactate production by IFNα-treated cells in vitro. These findings were recapitulated in whole-transcriptome sequencing data of human bladder tumors treated with intravesical Nadofaragene firadenovec. Lipidomics performed on murine MB49 tumors treated with poly(I:C) identified 79 upregulated lipids, including phosphotidyl choline, spingomyelin and phosphatidyl ethanolamine, and 12 downregulated lipids, notably the cardiolipin class. Lipidomics performed on patient urine samples collected pre- and post-treatment with intravesical Nadofaragene firadenovec detected &gt;592 lipids with distinct expression profiles differentiating clinical responders and non-responders at both timepoints. Conclusions: We describe novel modulation of glucose and lipid metabolism by bladder tumor cells in response to IFNα gene therapy. These metabolic changes were reproducible across in vitro, in vivo and clinical trial studies and improve our mechanistic understanding of IFNα gene therapy, identify tumor escape pathways targetable with combination therapy regimens, and identify a new class of biomarkers for predicting clinical response of NMIBC to IFNα gene therapy.
Performances of NeuMoDx™, a random-access system for hepatitis B virus DNA and hepatitis C virus RNA quantification
Authors: Juliette Besombes, Charlotte Pronier, Charles Lefevre, Gisèle Lagathu, Anne Maillard, Claire Grolhier, Vincent Thibault
Journal: Clinical Microbiology and Infection (2021)

Monitoring of viral loads (VL) for hepatitis B and C viruses (HBV; HCV) is essential to evaluate disease progression and treatment response. Automated, random-access rapid systems are becoming standard to provide clinicians with reliable VL. The aim of this study was to evaluate the analytical performances of the recently launched NeuMoDx™ for HBV-DNA and HCV-RNA quantification.Clinical samples routinely quantified on the Beckman-Veris system were either retrospectively (frozen samples; HBV n = 178, HCV n = 249), or in parallel (fresh primary tubes; HBV n = 103, HCV n = 117) tested using NeuMoDx™. Linearity range was assessed on serial dilutions of high-titre plasmas containing different genotypes for HBV (A-E, n = 9) and HCV (1a,1b,2-5, n = 12).Overall test failure, mostly internal control amplification failure, was 2.3% and was not influenced by matrix types (fresh or frozen). For HBV VL, κ agreement was 74%, with 27 (12.6%) discrepancies. Correlation between HBV assays on 72 quantified samples by both methods was excellent (r = 0.963) with a mean bias (NeuMoDx™-Veris) of 0.21 log IU/mL. For HCV VL, κ agreement reached 94%, with 9 (2.8%) discrepancies. The r correlation factor between assays on 104 samples was 0.960 with a mean bias of -0.14 log IU/mL (NeuMoDx™-Veris). Serial dilutions confirmed the claimed linear ranges for all analysed HBV and HCV genotypes. The mean turnaround time was 72 minutes (range 55-101 minutes) for HBV and 96 minutes (range 78-133 minutes) for HCV.Results obtained on the NeuMoDx™ confirmed the overall good functionality of the system with a short turn-around-time, full traceability and easy handling. These results on HBV and HCV VL look promising and should be challenged with further comparisons.
Association of Ablative Radiation Therapy With Survival Among Patients With Inoperable Pancreatic Cancer
Authors: Marsha Reyngold, Eileen M. O’Reilly, Anna M. Varghese, Megan Fiasconaro, Melissa Zinovoy, Paul B. Romesser, Abraham Wu, Carla Hajj, John J. Cuaron, Richard Tuli, Lara Hilal, Danny Khalil, Wungki Park, Ellen D. Yorke, Zhigang Zhang, Kenneth H. Yu, Christopher H. Crane
Journal: JAMA Oncology (2021)

Surgical resection has been considered the only curative option for patients with pancreatic cancer. Nonoperative local treatment options that can provide a similar benefit are needed. Emerging radiation techniques that address organ motion have enabled curative radiation doses to be given in patients with inoperable disease.To determine the association of hypofractionated ablative radiation therapy (A-RT) with survival for patients with locally advanced pancreatic cancer (LAPC) treated with a novel radiation planning and delivery technique.This cohort study included 119 consecutive patients treated with A-RT between June 2016 and February 2019 and enrolled in a prospectively maintained database. Patients were treated with a standardized technique within a large academic cancer center regional network. All patients with localized, unresectable, or medically inoperable pancreatic cancer with tumors of any size and less than 5 cm luminal abutment with the primary tumor were eligible.Ablative RT (98 Gy biologically effective dose) was delivered using standard equipment. Respiratory gating, soft tissue image guidance, and selective adaptive planning were used to address organ motion and limit the dose to surrounding luminal organs.The primary outcome was overall survival (OS). Secondary outcomes included incidence of local progression and progression-free survival.Between 2016 and 2019, 119 patients (59 men, median age 67 years) received A-RT, including 99 with T3/T4 and 53 with node-positive disease, with a median carbohydrate antigen 19-9 (CA19-9) level greater than 167 U/mL. Most (116 [97.5%]) received induction chemotherapy for a median of 4 months (0.5-18.4). Median OS from diagnosis and A-RT were 26.8 and 18.4 months, respectively. Respective 12- and 24-month OS from A-RT were 74% (95% CI, 66%-83%) and 38% (95% CI, 27%-52%). Twelve- and 24-month cumulative incidence of locoregional failure were 17.6% (95% CI, 10.4%-24.9%) and 32.8% (95% CI, 21.6%-44.1%), respectively. Postinduction CA19-9 decline was associated with improved locoregional control and survival. Grade 3 upper gastrointestinal bleeding occurred in 10 patients (8%) with no grade 4 to 5 events.This cohort study of patients with inoperable LAPC found that A-RT following multiagent induction therapy for LAPC was associated with durable locoregional tumor control and favorable survival. Prospective randomized trials in patients with LAPC are warranted.
Dietary vitamin K is remodeled by gut microbiota and influences community composition
Authors: Jessie L. Ellis, J. Philip Karl, Angela M. Oliverio, Xueyan Fu, Jason W. Soares, Benjamin E. Wolfe, Christopher J. Hernandez, Joel B. Mason, Sarah L. Booth
Journal: Gut Microbes (2021)

Vitamins have well-established roles in bacterial metabolism. Menaquinones (MKn, n = prenyl units in sidechain) are bacterially produced forms of vitamin K produced by the gut microbiota and consumed in the diet. Little is known about the influence of dietary vitamin K quinones on gut microbial composition and MKn production. Here, male and female C57BL6 mice were fed a vitamin K deficient diet or vitamin K sufficient diets containing phylloquinone (PK, plant-based vitamin K form), MK4, and/or MK9. DNA was extracted from cecal contents and 16S sequencing conducted to assess microbial composition. Cecal microbial community composition was significantly different in vitamin K deficient female mice compared to females on vitamin K sufficient diets (all p < .007). Parallel trends were seen in male mice, but were not statistically significant (all p > .05 but <0.1). Next, stable isotope-labeled vitamin K quinones were supplemented to male and female C57BL6 mice (2H7PK, 13C11MK4, 2H7MK7, 2H7MK9) and to an in vitro fermentation model inoculated with human stool (2H7PK, 2H7MK4, 2H7MK9, or vitamin K precursor 2H8-menadione). Vitamin K quinones in feces and culture aliquots were measured using LC-MS. In vivo, supplemented vitamin K quinones were remodeled to other MKn (2H7- or 13C6-labeled MK4, MK10, MK11, and MK12), but in vitro only the precursor 2H8-menadione was remodeled to 2H7MK4, 2H7MK9, 2H7MK10, and 2H7MK11. These results suggest that dietary vitamin K deficiency alters the gut microbial community composition. Further studies are needed to determine if menadione generated by host metabolism may serve as an intermediate in dietary vitamin K remodeling in vivo.
A phase II study of first-line afatinib for patients aged 75 or older with EGFR mutation-positive advanced non-small cell lung cancer: North East Japan study group trial NEJ027
Authors: T. aiba, Y. Minegishi, O. Yamaguchi, S. Kuyama, S. Watanabe, K. Usui, M. Mori, O. Hataji, T. Nukiwa, S. Morita, K. Kobayashi, A. Gemma
Journal: Annals of Oncology (2018)