tbuckley/cabot-search huggingface dataset:
Final results of PEANUT: Pembrolizumab and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC).
Authors: Patrizia Giannatempo, Giuseppina Calareso, Marco Bandini, Laura Marandino, Daniele Raggi, Elena Farè, Maurizio Colecchia, Filippo Pederzoli, Andrea Gallina, Russell Madison, Alberto Briganti, Jeffrey S. Ross, Francesco Montorsi, Andrea Necchi
Journal: Journal of Clinical Oncology (2020)

5017 Background: Pembrolizumab (pembro) is a new standard of care in chemotherapy (CT) pre-treated patients (pts) with metastatic UC. Nab-paclitaxel demonstrated preliminary activity in advanced UC. In the PEANUT study (NCT03464734) we investigated their combination in advanced UC after CT failure. Methods: In an open-label, single-arm, phase 2 trial, pts received 200 mg pembro, intravenously (IV), on D1 and 125 mg/m 2 IV nab-paclitaxel on D1 and D8, every 3 weeks, until disease progression (PD) or unacceptable toxicity. Inclusion criteria were: predominant UC histology, failure of ≤2 platinum-based CT for metastatic disease. Response was evaluated by RECIST v.1.1 criteria every 2 cycles. Biomarkers included PD-L1 combined positive score (CPS) and comprehensive genomic profiling on tumor and blood samples (FoundationONE and FoundationACT assay). The primary endpoint was the progression-free survival (PFS). The target was to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). Results: Between 01 and 12/2019, PEANUT study enrolled 65 pts: 24% were female, median age was 69 yrs (IQR: 61-73); 25% had failed &gt; 1 prior systemic therapies; 35% had ECOG-performance status 1; 33% had liver metastases. The median TMB was 6.9 mut/Mb. After median follow-up (FUP) of 5.5 months, 34 pts have relapsed (52.3%). The median PFS was 5 months (95%CI: 3-not reached). The 3-month PFS was 60.7% (95%CI: 49.8-74.1). The confirmed objective response-rate (ORR) was 47.7% (95%CI: 35.2-60.4): 22 partial responses and 9 complete responses (13.8%). The median duration of response was not reached, and 4 pts (6.1%) are long-term responders ( &gt; 12 months). Grade 3 treatment-related adverse events (TRAE) were seen in 20 pts (30.7%). Most common any-grade TRAE included alopecia (76%), neutropenia (33.3%) and asthenia (33%). Neither TMB nor CPS were significantly associated with PFS on univariable analyses. In matched tumor/blood samples, objective responses were seen in 8/10 pts with PI3KCA mutations (80%); 6/10 pts with RB1 alterations (60%); 5/12 pts with DNA damage repair gene alterations (41.7%). Conclusions: Pembro-nab-paclitaxel, the first salvage CT-immunotherapy combination in UC, demonstrated a good tolerability, promising PFS and a clinically meaningful ORR in II-III line setting of advanced UC. As more mature data on biomarker selection emerges, this combination warrants additional studies in either second-line or earlier disease settings. Clinical trial information: NCT03464734 .
Abstract 15466: Do No Harm: Defibrillator Knowledge, Gender, and Device-Related Concerns
Authors: Jennifer L Miller, Misook Lee L Chung, Muna H Hammash, Melanie Schrader, Debra K Moser
Journal: Circulation (2019)

Introduction: Implantable cardioverter defibrillator (ICD) recipients live with uncertainty about their future and concerns related specifically to the function of this life-saving/extending device...
Impact of DNA damage repair (DDR) mutations on treatment outcomes in men receiving conventional therapy for metastatic castration resistant prostate cancer (mCRPC).
Authors: Alex S. Carlson, Rigo Acevedo, Daniel M. Lim, Roman Gulati, Evan Y. Yu, Michael Thomas Schweizer
Journal: Journal of Clinical Oncology (2020)

172 Background: Nearly 25% of patients with mCRPC harbor DDR alterations, with some of these mutations associating with increased tumor susceptibility to PARP inhibitors and platinum-based chemotherapies. While, mutations in some DDR genes (e.g. BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating DDR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ASIs) or taxane-based chemotherapy have yielded conflicting results. Methods: We conducted a single center retrospective analysis to assess clinical outcomes to standard therapies in mCRPC patients with/without DDR mutations as determined on clinical grade next-generation sequencing assays. The primary endpoint was PSA50 response (i.e. ≥50% PSA reduction from baseline), estimated using Bayesian logical regression; secondary endpoints included PSA progression-free survival (PFS), estimated using Kaplan-Meier methods. Results: A total of 93 patients were included in this analysis, with DDR mutations identified in 40/93 (43%). No significant correlations were found between DDR status and PSA50 response within treatment modalities even after adjusting for receipt of prior therapies within the same class (Table). DDR status was not associated with PSA PFS in patients treated with ASIs. There was evidence of decreased PFS in patients with BRCA1/2 and PALB2 mutations treated with Docetaxel (p = 0.008) and Cabazitaxel (p = 0.005), but limited patient numbers precluded significant pairwise analysis with Cabazitaxel. Conclusions: DDR gene mutational status was not associated with inferior clinical outcomes following treatment with ASIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.[Table: see text]
Selection of pesticides to reduce human and environmental health risks: a global guideline and minimum pesticides list
Authors: Paul C Jepson, Katie Murray, Oliver Bach, Maria A Bonilla, Lars Neumeister
Journal: The Lancet Planetary Health (2020)

BackgroundPesticides present widespread risks to human and environmental health, yet selection criteria for end-users that factor in differences in risk between compounds are scant. We developed a system to classify pesticide risks and hazards with respect to human and environmental health and produce a minimum (lower risk) pesticide list.MethodsWe classified 659 pesticides by acute and chronic risks to human health (eg, respiratory and carcinogenic effects) and by environmental risks, including biomagnification and atmospheric ozone depletion and risks to aquatic life, terrestrial wildlife, and pollinators. From this analysis, we produced a guideline for selection of lower risk pesticides. The classification of highly hazardous and high-risk compounds has been tested in more than a million farm households in the tropics, and in US integrated pest management (IPM) programmes. The full classification, including the minimum pesticide list, has been used in management of the fall armyworm (Spodoptera frugiperda) throughout Africa and Asia.FindingsOur analysis developed a stand-alone guideline for selection of lower risk pesticides. When classifying pesticides in current use against the fall armyworm in Africa, our guideline identified chemicals that are effective and of lower risk to human and environmental health. We argue that a minimum (lower risk) pesticides list, which meets IPM needs, could be developed from our classification system.InterpretationAs far as we are aware, our analysis is the first to propose a method for implementing the idea of a minimum pesticide list and the first to outline lower risk candidate compounds. Currently accepted criteria for defining highly hazardous pesticides do not adequately protect human bystanders, aquatic life, terrestrial wildlife, and pollinators.FundingThe Sustainable Agriculture Network, the Rainforest Alliance, the US Department of Agriculture-National Institute of Food and Agriculture, the US Department of Agriculture, the Foreign Agricultural Service, the US Agency for International Development, the International Maize and Wheat Improvement Center, and the UN Food and Agriculture Organization.
Fecal IgA Levels Are Determined by Strain-Level Differences in Bacteroides ovatus and Are Modifiable by Gut Microbiota Manipulation
Authors: Chao Yang, Ilaria Mogno, Eduardo J. Contijoch, Joshua N. Borgerding, Varun Aggarwala, Zhihua Li, Sophia Siu, Emilie K. Grasset, Drew S. Helmus, Marla C. Dubinsky, Saurabh Mehandru, Andrea Cerutti, Jeremiah J. Faith
Journal: Cell Host & Microbe (2020)
Investigating the role of the gastrointestinal microbiome in response to immune checkpoint inhibitors (ICIs) among patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Anika Agarwal, Jennifer Modliszewski, Lauren Davey, Marco Reyes-Martinez, Daniella Runyambo, David Corcoran, Holly Dressman, Daniel J. George, Raphael Valdivia, Andrew J. Armstrong, Tian Zhang
Journal: Journal of Clinical Oncology (2020)

730 Background: ICIs are effective in mRCC, but one pertinent clinical need is to identify predictive biomarkers for response. The PD-1 receptor has been implicated in regulating gastrointestinal commensal bacteria, with varied immune interactions, thereby impacting response to ICIs. We evaluated bacterial taxa and ICI outcomes in mRCC pts. Methods: Fecal samples from 22 mRCC pts were collected at baseline, week (wk)-4 on ICI, and upon disease progression. Pts were grouped as responders (R, complete or partial response) or non-responders (NR, stable or progressive disease). Microbial DNA was isolated by next generation DNA sequencing. The V4 region of bacterial 16S ribosomal RNA was amplified from extracted DNA and analyzed for bacterial abundance, as well as alpha diversity indices (number of amplicon sequence variants [ASVs], Shannon’s Index, Faith’s Phylogenetic Diversity, and Pielou’s evenness) and beta diversity indices on ASVs (Bray-Curtis, Jaccard, and unweighted/weighted UniFrac dissimilarity measures). Results: Beta diversity analysis at baseline showed no difference in microbial composition between Rs and NRs. However, beta diversity analysis did show a significant change in composition from baseline to wk 4 in R vs NR pts (Bray Curtis p-value=0.03). Among mRCC pts with CR to ICIs, counts of bacteria in the phylum Verrucomicrobia had an upward trend from baseline to wk 4. All mRCC pts with CR (n=3) had Akkermansia at wk 4. However, Akkermansia colonization was not sufficient for response, present in 7/9 Rs and 6/11 NRs. Conclusions: Baseline microbiome differences between ICI Rs and NRs are not enough to predict outcomes. Diversity changes between baseline and wk-4 on treatment could be an early predictor of response. Factors other than presence of Akkermansia (tumor or host-specific, Akkermansia strain variation, or other bacteria in the microenvironment) may contribute to response. Further species and strain-level profiling of the microbiota, tumor-specific genomic alterations, host immune response, and increasing sample size of ICI-treated patients may improve detection of significant differences between Rs and NRs.
A phase Ib/II open-label study of tazemetostat (TAZ) plus enzalutamide (E) or abiraterone/prednisone (A/P) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Wassim Abida, Thomas Paul Bradley, Arash Rezazadeh, Lawrence Ivan Karsh, Ashley Ross, Daniel Saltzstein, Evren Kocabas Argon, Anthony Hamlett, Jeanie Tang, Deyaa Adib
Journal: Journal of Clinical Oncology (2020)

TPS255 Background: The histone methyltransferase EZH2 is overexpressed in many cancers. In prostate cancer (PC), EZH2 inhibition may reverse acquired resistance to androgen inhibitors (AIs). Pts may initially respond to AIs, but pts who progress have limited treatment options. In phase 2 trials, TAZ, a selective, orally bioavailable, investigative small molecule EZH2 inhibitor, has demonstrated encouraging objective responses in B-cell lymphomas and molecularly defined solid tumors and a favorable safety profile. In PC preclinical models, TAZ + E or A/P showed a greater reduction in tumor growth than either drug alone. This study will evaluate the safety and efficacy of TAZ + E or A/P vs E or A/P alone in mCRPC. Methods: This phase 1b/2 study will enroll pts ≥18 years with progressive mCRPC, with or without prior second-generation AI treatment, and no prior chemotherapy. Phase 1b will identify the recommended phase 2 dose (RP2D) of TAZ when combined with E (160 mg/day) or A/P (A: 1000 mg/day; P: 5 mg twice-daily [BID]) and evaluate the safety and tolerability of each combination in treatment-naïve pts and pts previously treated with a second-generation AI. Using a modified 3+3 design (up to 48 pts: 18 for TAZ+A/P and 30 for TAZ+E), TAZ dosing will start at 400 mg BID, escalating to 800 mg BID in the TAZ+A/P group or 1600 mg BID in the TAZ + E group, if no dose-limiting toxicities are observed. Phase 2 will begin once the RP2D for each combination is determined. Efficacy and safety results from phase 1b will inform the final design for phase 2. Phase 2 will be an open label study where pts will be randomized to either E or A/P alone or in combination with TAZ. TAZ will be administered at the RP2D in continuous 28-day cycles for as long as pts tolerate treatment and continue AI therapy. Tumor assessments will be performed every 9 weeks for 6 months and every 12 weeks thereafter. Efficacy assessments include radiographic progression-free survival (primary endpoint), prostate-specific antigen (PSA) ≥50% response rate, time to PSA progression, time to subsequent systemic therapy, and objective response rate. Safety is a secondary endpoint.
Mechanisms by which Obesity Dysregulates Immunometabolic State in Asthma
Authors: Sarah Henrickson, Kaitlin O'Boyle, Peyton Conrey, Sasikanth Manne, Bertram Bengsch, Frank Mentch, Ramin Herati, Ting Qian, Laura Vella, Christopher Pastore, Li-Yin Hung, Samir Sayed, De'Broski Herbert, Aaron Masino, Scott Hensley, Hakon Hakonarson, Joshua Rabinowitz, Susan Coffin, E. John Wherry
Journal: Journal of Allergy and Clinical Immunology (2020)
Quality and Safety in Healthcare, Part LXVI
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2020)

Problems in the learning environment are the main contributing factors to medical student burnout. These issues include stresses from mistreatment, poor support, cynical supervisors, pressure to get good grades and learn a huge amount of information quickly, fatigue, lack of control, and so on. Personal risk factors include having been seriously ill recently, having a low grit score, being in debt, and having a job.
Prevention of docetaxel-associated febrile neutropenia with primary granulocyte colony-stimulating factors (GCSF) in Chinese metastatic hormonal-sensitive (mHSPC) and castration-resistant prostate cancer (mCRPC).
Authors: Darren M.C. Poon, Kuen Chan, T.W. Chan, Bryan Ng, S Wai-kwan Siu, Joyce Ng, David Johnson, Ka Chai Lee
Journal: Journal of Clinical Oncology (2020)

72 Background: Plenty reports suggest Asian prostate cancer patients are more susceptible to docetaxel-related febrile neutropenia (FN). However, primary GCSF prophylaxis is currently not recommended by international guidelines for patients with mCRPC or mHSPC when docetaxel is administered. Therefore, we aim to evaluate the potential benefit of primary GCSF in preventing the potentially life-threatening FN for Chinese mHSPC and mCRPC treated with docetaxel. Methods: Two cohorts (2003-2012 &amp; 2015-2018) that consisted of Chinese patients with mHSPC and mCRPC who had docetaxel at six public oncology centres in Hong Kong were grouped and analysed. Primary GCSF was defined as its administration within 5 days of beginning docetaxel, and its use was at the discretion of oncologists. The primary outcome was FN within 21 days of first cycle of docetaxel (1st FN). Multivariable regression analysis was used. Results: A total of 377 metastatic prostate cancer (mHSPC, n=100 (26%); mCRPC, n=277 (73%)) patients with docetaxel treatment was identified. Primary GCSF was given in 71 (18%) patients. The baseline characteristics were balanced between groups with and without primary GCSF. FN was happened in 61 patients (16%), with 37 (9%) of them at 1st cycle. Primary GCSF were administered in 2 and 69 patients with and without 1 st FN, respectively (5.4% vs 20.3%, p=0.03). Primary GCSF was associated with reduced risk of 1st FN (odds ratio (OR), 0.22; 95% CI 0.05 - 0.96; p=0.04) in overall, and a similar trend was observed in both mHSPC (OR, 0.36; p=0.35) and mCRPC (OR, 0.16, p=0.08) subgroups. Besides, among various clinical parameters, poor performance status (ECOG 2-3) was associated with increased risk of 1st FN (OR, 3.90, 95% CI 1.66 – 9.13, p=0.002). Conclusions: Primary GCSF prophylaxis is suggested for Asian mCRPC and mHSPC patients, particularly those with poor performance status, to alleviate the risk of docetaxel-related febrile neutropenia.
The effect of androgen deprivation therapy on 68GA-PSMA-tracer uptake in nonmetastatic prostate cancer patients.
Authors: Onal Cem, Ozan Cem Guler, Nese Torun, Mehmet Reyhan, Ali Fuat Yapar
Journal: Journal of Clinical Oncology (2020)

22 Background: To evaluate the effect of neoadjuvant androgen deprivation treatment (ADT) on prostate specific membrane antigen (PSMA) tracer uptake demonstrated in 68 Ga-PSMA-positron emission tomography (PET/CT) in non-metastatic hormone-naïve prostate cancer patients. Methods: The clinical data of 108 prostate cancer patients who received neoadjuvant ADT were retrospectively analyzed. All patients had a baseline 68 Ga-PSMA-PET/CT scan and a second scan was delivered median of 2.9 months after initiation of ADT. Patients with clinical and radiological evidence of distant metastasis were excluded from the study. The maximum standardized uptake value (SUV max ) of primary tumor (SUV p ) and metastatic lymph nodes (SUV ln ) as well as PSA response were assessed between pre- and post-ADT 68Ga-PSMA-PET/CT scans. Results: The median SUV p and SUV ln were 14.0 (range, 4.9 – 78.4) and 13.2 (range, 3.6 – 64.5), respectively. There was a significant moderate correlation between baseline serum PSA and SUV p (Spearman = 0.513, p&lt;0.001). There were significant decreases in post-treatment serum PSA, SUV p , and SUV p . A decrease in SUV p was seen in 91 patients (84%) with a median value of 66% (range, 5% – 100%), while 17 patients (16%) had no change in or an increase in PSMA tracer uptake with a median value of 24% (range, 0% – 198%). Patients with Gleason score (GS) of 7 had significantly higher metabolic response rates compared to other patients. The disease progression was significantly higher only in patients with GS &gt; 7 disease compared to GS 7 disease. The PSA response to ADT was lowest in patients with ISUP high-grade tumors. A total of 16 patients (15%) had progressive disease, and in 9 patients (8%), radiotherapy decisions were modified according to post-treatment 68 Ga-PSMA-PET/CT scans. Conclusions: The current study includes the largest number of patients analyzed to date and demonstrates that ADT causes a significant decrease in serum PSA values and SUV p and SUV ln . The authors demonstrate that 68 Ga-PSMA-PET/CT may be used as a quantitative imaging modality after neoadjuvant ADT in hormone-naïve non-metastatic PC patients.
NFE2L2 Interacts with Second Hand Smoke Exposure to Increase the Risk and Severity of Pediatric Asthma
Authors: Elisabet Johansson, Jocelyn Biagini Myers, Lisa Martin, Hua He, Matthew Weirauch, Xiaoting Chen, Gurjit Khurana Hershey
Journal: Journal of Allergy and Clinical Immunology (2020)
Digital cholangioscopy-guided retrieval of a migrated hepaticogastrostomy stent through a created hepaticogastrostomy route
Authors: Tomotaka Saito, Tsuyoshi Hamada, Hirofumi Kogure, Yousuke Nakai, Kazuhiko Koike
Journal: Endoscopy (2020)

Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is increasingly utilized for benign biliary diseases in cases with surgically altered anatomy [1] [2], but stent migration is a potential complication [3]. We describe successful retrieval of a migrated hepaticogastrostomy stent through a newly created EUS-HGS route using a digital cholangioscope.
Extrahepatic cholangiography in near-infrared II window with the clinically approved fluorescence agent indocyanine green: a promising imaging technology for intraoperative diagnosis
Authors: Di Wu, Dingwei Xue, Jing Zhou, Yifan Wang, Zhe Feng, Junjie Xu, Hui Lin, Jun Qian, Xiujun Cai
Journal: Theranostics (2020)

: Biliary tract injury remains the most dreaded complication during laparoscopic cholecystectomy. New intraoperative guidance technologies, including near-infrared (NIR) fluorescence cholangiography with indocyanine green (ICG), are under comprehensive evaluation. Previous studies had shown the limitations of traditional NIR light (NIR-I, 700-900 nm) in visualizing the biliary tract structures in specific clinical situations. The aim of this study was to evaluate the feasibility of performing the extrahepatic cholangiography in the second NIR window (NIR-II, 900-1700 nm) and compare it to the conventional NIR-I imaging.
Comprehensive understanding of magnetic hyperthermia for improving antitumor therapeutic efficacy
Authors: Xiaoli Liu, Yifan Zhang, Yanyun Wang, Wenjing Zhu, Galong Li, Xiaowei Ma, Yihan Zhang, Shizhu Chen, Shivani Tiwari, Kejian Shi, Shouwen Zhang, Hai Ming Fan, Yong Xiang Zhao, Xing-Jie Liang
Journal: Theranostics (2020)

Magnetic hyperthermia (MH) has been introduced clinically as an alternative approach for the focal treatment of tumors.MH utilizes the heat generated by the magnetic nanoparticles (MNPs) when subjected to an alternating magnetic field (AMF).It has become an important topic in the nanomedical field due to their multitudes of advantages towards effective antitumor therapy such as high biosafety, deep tissue penetration, and targeted selective tumor killing.However, in order for MH to progress and to realize its paramount potential as an alternative choice for cancer treatment, tremendous challenges have to be overcome.Thus, the efficiency of MH therapy needs enhancement.In its recent 60-year of history, the field of MH has focused primarily on heating using MNPs for therapeutic applications.Increasing the thermal conversion efficiency of MNPs is the fundamental strategy for improving therapeutic efficacy.Recently, emerging experimental evidence indicates that MNPs-MH produces nano-scale heat effects without macroscopic temperature rise.A deep understanding of the effect of this localized induction heat for the destruction of subcellular/cellular structures further supports the efficacy of MH in improving therapeutic therapy.In this review, the currently available strategies for improving the antitumor therapeutic efficacy of MNPs-MH will be discussed.Firstly, the recent advancements in engineering MNP size, composition, shape, and surface to significantly improve their energy dissipation rates will be explored.Secondly, the latest studies depicting the effect of local induction heat for selectively disrupting cells/intracellular structures will be examined.Thirdly, strategies to enhance the therapeutics by combining MH therapy with chemotherapy, radiotherapy, immunotherapy, photothermal/photodynamic therapy (PDT), and gene therapy will be reviewed.Lastly, the prospect and significant challenges in MH-based antitumor therapy will be discussed.This review is to provide a comprehensive understanding of MH for improving antitumor therapeutic efficacy, which would be of utmost benefit towards guiding the users and for the future development of MNPs-MH towards successful application in medicine.