tbuckley/cabot-search huggingface dataset:
First assessment of the stool mycobiome in patients (pts) with metastatic renal cell carcinoma (mRCC) receiving targeted therapy (TT) or immunotherapy (IO).
Authors: Nazli Dizman, Joann Hsu, John D Gillece, Megan Folkerts, Lauren J Reining, Paulo Gustavo Bergerot, Luis A Meza, Zeynep Busra Zengin, Ramya Muddasani, Neal Chawla, Misagh Karimi, Jeffrey M. Trent, Sarah K Highlander, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2021)

337 Background: Previous studies have associated specific stool bacterial species with response to both targeted therapy and immunotherapy (Routy et al Science 2018; Dizman et al Cancer Med 2020). Abundant fungal elements also constitute the human microbiome (the so-called “mycobiome”); we explore whether these could be related to clinical benefit (CB) from TT. Methods: Pts from 2 simultaneously conducted studies were included in the analysis. Both studies enrolled patients with histologically confirmed RCC with metastatic disease; in one study, pts received standard of care (SOC) TT, while in the other pts received SOC IO. In both studies, stool was collected at baseline and at multiple timepoints thereafter. Whole metagenome sequencing was performed for fungal microbiome composition (TGen North, AZ). Linear discriminant analysis (LDA) effect size (LEfSe) was used for comparison of the gut mycobiome in patients who obtained clinical benefit (CB; complete response, partial response or stable disease &gt; 6mos) versus no clinical benefit (NCB; progressive disease or stable disease ≤6mos) from TT or IO. Results: A total of 50 samples from 24 pts (19:5 M:F) were included in the analysis. The majority of pts (19; 79%) had clear cell histology. 15 pts received TT while 9 pts received IO. The fungal genera demonstrating the highest abundance was Saccharomyces with a median relative abundance of 86.9% (range, 11%-99%). LEfSe performed in different taxonomic levels revealed Malassezia globosa (LDA = 4.93; P = 0.038) and Alternaria infectoria (LDA 4.94; P = 0.018) as gut mycobiome components associated with NCB, and order Russulales associated with CB from TT (LDA = 4.93; P = 0.018). In contrast, no association was identified between mycobiome profile and CB in the IO-treated group. The presence of several pathogenic fungi such as Candida albicans and Aspergillus fumigatus was noted in a minority of pts and did not have any bearing on clinical outcome. In pts with serial samples, a trend towards decreasing Saccharomyces spp. (the most abundant species) and increasing fungal diversity was noted. Conclusions: Our study is the first to highlight potential associations between the mycobiome and CB with TT. Our finding of Malassezia spp resulting in lack of CB with TT bolsters findings from Aykut et al (Nature 2019), implicating the same genera in progression of pancreatic cancer. Confirmation of these findings in larger series is underway.
Open Schools, Covid-19, and Child and Teacher Morbidity in Sweden
Authors: Lonni Besançon, David Steadson, Antoine Flahault
Journal: New England Journal of Medicine (2021)

We argue that the focus on morbidity is of limited relevance to analyze the effects of school closure on COVID-19 transmission.Children are equally susceptible, and similarly likely to transmit COVID19 as adults [1].Decisions to close schools were based on an attempt to limit the spread of the virus [2].Consequently, to investigate the efficiency of measures on schools, the outcome of an analysis should logically be on outbreaks or household transmission and assessing the direct or indirect effects of schools on it.Currently, household transmission is only mentioned as a limitation of the analysis.Outbreaks, on the other hand, are not discussed despite recent data for weeks 46-50 from the Swedish Public Health Agency reporting a total of 467 outbreaks in schools (highschools excluded), which corresponds to 48% of all the reported outbreaks in this period (967) [3].This directly contradicts findings from the authors and should consequently be discussed along with other recent contradictory findings (see, e.g., [1]).
Current prevalence and relevance of positive patch test reactions to cosmetic and noncosmetic isothiazolinones in the UK
Authors: L.F. Soriano, M.M.U. Chowdhury, S.M. Cooper, P. Cousen, S. Dawe, A. Havelin, C.R. Holden, G.A. Johnston, D.I. Orton, A. Ramoutar, N.M. Stone, D.A. Thompson, D.A. Buckley
Journal: British Journal of Dermatology (2021)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
An NRP1/MDM2‐Targeted D‐Peptide Supramolecular Nanomedicine for High‐Efficacy and Low‐Toxic Liver Cancer Therapy
Authors: Yunjiang Zhou, Yaxin Chen, Yingying Tan, Rong Hu, Miao‐Miao Niu
Journal: Advanced Healthcare Materials (2021)

Abstract Supramolecular nanomedicines based on self‐assembly of D‐peptides have been of great interest as potential candidates for cancer therapy. Neuropilin‐1 (NRP1) and mouse double minute 2 (MDM2) have been considered as the anticancer targets because of their overexpression in cancers. However, NRP1/MDM2‐targeted D‐peptide supramolecular nanomedicines remain unreported. Here, a potent anticancer D‐peptide supramolecular nanomedicine targeting NRP1 and MDM2, termed as NMTP‐5, is identified by using structure‐based virtual screening techniques. NMTP‐5 exhibits good biostability and strong cellular uptake performance. Moreover, NMTP‐5 displays strong anticancer activity to SK‐Hep‐1 cells in vitro and in vivo, with no apparent host toxicity. This work demonstrates that NMTP‐5 can be used as a potential chemotherapeutic agent for the treatment of liver cancer.
Abstract 10587: A Suggested Redosing Interval of Del Nido Cardioplegia Solution in Adult Cardiac Surgery: A Propensity-matched Study
Authors: Takeyoshi Ota, Hiroto Kitahara, Hidefumi Nishida, Valluvan Jeevanandam
Journal: Circulation (2019)

Introduction: While del Nido cardioplegia (DN) has been utilized in adult cardiac surgery recently, few studies have described proper maintenance dose intervals. The purpose of this study was to as...
Pre-orchiectomy serum tumor markers as a predictor of recurrence in stage I germ cell tumors.
Authors: Rohit R Badia, Rashed Ghandour, Jeffrey Howard, Joseph G Cheaib, Ragheed Saoud, Scott E. Eggener, Nirmish Singla, Phillip M. Pierorazio, Aditya Bagrodia
Journal: Journal of Clinical Oncology (2021)

389 Background: Organ confined (stage IA/IB) testicular cancer has a high cure rate regardless of initial treatment modality, making it important to weigh the toxicities of treatment against potential benefits. While many clinicians routinely obtain serum tumor markers (STMs) prior to radical orchiectomy, their role in predicting recurrence in stage IA and IB testicular cancer has not been studied. Methods: A multi-institutional database of stage I testicular cancer patients diagnosed between 2006 and 2018 was created. Univariate and multivariate regression models were created to understand which factors predict recurrence. Recurrence analyses using Kaplan-Meier curves for elevated and normal pre-orchiectomy STMs were also generated. Results: 150 patients met the study criteria, of whom 16 (11%) relapsed (Table). 9 (56%) patients with recurrence had elevated pre-orchiectomy STMs, and 7 (44%) had normal pre-orchiectomy STMs. Similarly, 75 patients (56%) without relapse had elevated pre-orchiectomy STMs. Of 9 patients with elevated pre-orchiectomy STMs, 6 (67%) had normal STMs at recurrence; of 7 with normal pre-orchiectomy STMs, 4 patients (57%) had elevated STMs at recurrence. On Kaplan-Meier analysis, no association between level of pre-orchiectomy STMs and recurrence free survival was observed. Conclusions: Pre-orchiectomy STMs were not independently associated with recurrence in stage I testis cancer. Interestingly, there was also no association between positivity of pre-orchiectomy STMs and whether or not STMs were elevated at recurrence. These findings support the continued use of standard-of-care imaging and STMs in surveillance of stage IA/IB testicular cancer patients regardless of pre-orchiectomy STMs. [Table: see text]
Association between Longer Travel Distance for Transplant Care and Access to Kidney Transplantation and Graft Survival in the United States
Authors: Adrian M. Whelan, Kirsten L. Johansen, Sandeep Brar, Charles E. McCulloch, Deborah B. Adey, Garrett R. Roll, Barbara Grimes, Elaine Ku
Journal: Journal of the American Society of Nephrology (2021)

Transplant candidates may gain an advantage by traveling to receive care at a transplant center that may have more favorable characteristics than their local center. Factors associated with longer travel distance for transplant care and whether the excess travel distance (ETD) is associated with access to transplantation or with graft failure are unknown.
Abstract PO-052: Exploring patient derived xenografts based pharmacogenomic data for precision oncology
Authors: Arvind Singh Mer, Benjamin Haibe-Kains
Journal: Clinical Cancer Research (2021)

Abstract Preclinical cancer models play a vital role in oncology research and precision medicine. Patient-derived tumor xenografts (PDXs) are used as reliable preclinical models for studying tumor biology and for testing anti-cancer therapies that are tailored according to genomic characteristics of tumors. Several academic groups, research institutes, and commercial organizations are generating and distributing PDX models. However the distributed nature of PDX model generation and lack of central repository make it challenging to find PDX models with specific characteristics. Furthermore this also hinders meta-analysis (across datasets) of PDX pharmacogenomic data. International consortia and catalogs of PDX models such as PDXNet, EurOPDX and PDXFinder are being developed to standardize PDX associated metadata and facilitate material sharing. Recently we have developed Xenograft Visualization &amp; Analysis (Xeva), an open-source software package in R programming language. Xeva allows PDX growth curve visualization, different response metrics computation and biomarker discovery. Extending to this we have developed XevaDB, a database of PDX drug response and genomic profiles. XevaDB is the first resource to allow concurrent visualization of drug response and associated molecular data such as mutation and copy number alterations. Furthermore XevaDB enables exploration of the tumor growth curve of a PDX model, along with corresponding control. XevaDB contains PDXs from &amp;gt;600 individual patients, spanning across nine different tissue types and &amp;gt;70 drugs. Using XevaDB, we have performed meta-analysis of PDX pharmacogenomic data and have identified 90 pathways significantly associated with response to 53 drugs (FDR &amp;lt; 5%). Our results show that activity of the EGFR signaling pathway is significantly associated with erlotinib response in lung cancer PDXs. We have also found that in PDXs, response to binimetinib is associated with the MAP kinase activation pathway. XevaDB provides a comprehensive resource to search and explore PDX pharmacogenomic data. By combining drug response with genomic data of PDXs, XevaDB allows researchers to quickly find the model of interest and access the data to answer their biological questions. As PDXs based pharmacogenomic datasets continue to expand, XevaDB will facilitate easy access and analysis of this valuable data by the scientific community. Citation Format: Arvind Singh Mer, Benjamin Haibe-Kains. Exploring patient derived xenografts based pharmacogenomic data for precision oncology [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-052.
Simultaneous endoscopic ultrasound-guided treatment of intestinal and biliary obstruction due to massive lymphoma of the duodenal papilla
Authors: Artur Raiter, Joanna Szełemej, Katarzyna Kozłowska-Petriczko, Jan Petriczko, Katarzyna M. Pawlak
Journal: Endoscopy (2021)

Since endoscopic ultrasound (EUS)-guided anastomoses of the gastrointestinal (GI) tract were first performed for biliary [1] and GI outlet obstructions [2], reported data have confirmed its safety and efficacy as an alternative modality for selected patients [3].
A Middle-aged Woman With Recurrent Chest Pain With Troponin Elevation and Unobstructed Coronary Arteries
Authors: Jun Hua Chong, Andreas Baumbach, Mohammed Y. Khanji
Journal: JAMA Cardiology (2021)

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Mononuclear phagocytic system and fibrosis: back to the future?
Authors: Kjetil Ask, Megan Vierhout, Anna Dvorkin-Gheva, Wei Shi
Journal: European Respiratory Journal (2021)

Bronchiolitis obliterans syndrome (BOS) is a chronic lung allograft dysfunction following lung transplantation [1–3], with histopathological characteristics of obliterative bronchiolitis (OB) that includes small airway epithelial disruption, submucosal inflammation and fibrosis, and obstruction of airway lumen. Clinical diagnosis is based on persistent decline of the allograft lung function measured by forced expiratory volume in 1 s and/or forced expiratory flow at 25–75% of forced vital capacity. 50% or more of lung transplantation recipients who survive beyond 5 years develop BOS, accounting for significant cases of lung transplantation failure and the leading cause of death for recipients who survived beyond 1 year after transplantation [4]. The mononuclear phagocytic system is a key player in fibrotic disease <https://bit.ly/3nVIlbQ>
A phase I/II study of combination olaparib and radium-223 in men with metastatic castration-resistant prostate cancer with bone metastases (COMRADE): A trial in progress.
Authors: Justin Shaya, Wanling Xie, Biren Saraiya, Mamta Parikh, Edmund Folefac, Adam C. Olson, Atish Dipankar Choudhury, David Johnson Einstein, Elisabeth I. Heath, Rahul Atul Parikh, Charles Kunos, S. Percy Ivy, Patricia LoRusso, Razelle Kurzrock, Geoffrey Shapiro, Rana R. McKay
Journal: Journal of Clinical Oncology (2021)

TPS182 Background: Radium-223 is an α-emitting radioisotope that induces DNA double-stranded breaks leading to cell death and has demonstrated improvement in overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. PARP inhibitors, including olaparib and rucaparib, inhibit repair of DNA single-stranded beaks and have demonstrated clinical efficacy in mCRPC patients harboring alterations in the homologous recombination repair (HRR) pathway. In extensive preclinical cancer models, PARP inhibitors have shown efficacy as radiosensitizing agents. We designed a phase 1/2 trial to test the clinical hypothesis that the combination of radium-223 with olaparib will demonstrate anti-tumor activity in patients with mCRPC irrespective of underlying HRR deficiency status. Methods: This is an open label, multi-center, phase 1/2 study (NCT03317392) evaluating the dosing, safety and efficacy of olaparib in combination with radium-223 in men with mCRPC with bone metastases. Patient must have 2 or more bone metastases and at least 1 bone metastasis that has not been treated with prior radiation therapy. Key exclusion criteria include the presence of visceral metastases or malignant lymphadenopathy exceeding 4 cm and prior therapy with radium-223 and/or PARP inhibitors. The phase 1 component of the study uses a 3+3 dose escalation design to determine the recommended phase 2 dose of olaparib in combination with standard of care dosing of Radium-223. The primary endpoint of the phase 1 component is safety. The phase 2 component of the study is an open-label, randomized study evaluating the combination of olaparib and radium-223 compared to radium-223 alone. The primary endpoint of the phase 2 component is radiographic progression-free survival as defined by Prostate Cancer Working Group 3 guidelines for bone metastases and RECIST v1.1 for non-bone metastases. Secondary endpoints include time to PSA progression, PSA response, time to subsequent therapy, time to first skeletal event, overall survival, and safety. Exploratory endpoints include stratification of response based on HRR alterations, whole exome sequencing of plasma cell free DNA both at baseline, on treatment, and at progression, and evaluation of changes in the tumor immune microenvironment with therapy. As of October 1, 2020, the phase 1 component has completed accrual and we anticipate opening the phase 2 component by December 2020. Clinical trial information: NCT03317392.
ICEPAC: A phase II multicenter study of avelumab combined with stereotactic ablative body radiotherapy (SABR) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Arun Azad, Lavinia Anne Spain, Angelyn Anton, Chun Loo Gan, Linda Garrett, Deborah Chang, Caitlin Bennett, Gargi Kothari, Mark Shaw, Phillip Parente, Carmel Jo Pezaro, Ben Tran, Shankar Siva, Edmond Michael Kwan
Journal: Journal of Clinical Oncology (2021)

86 Background: Studies investigating immune checkpoint inhibitors (ICI) in mCRPC have produced modest results. Radiation therapy may be synergistic with ICIs. We hypothesised that SABR would enhance anti-tumour activity of PD-L1 inhibitor avelumab in patients (pts) with progressive mCRPC. Methods: This phase II, single arm, multicentre study enrolled mCRPC pts following progression on ≥1 novel androgen receptor-directed therapy. Up to two lines of prior taxane chemotherapy were permitted. Pts received avelumab 10mg/kg IV q2weeks for a total of 24 weeks (12 cycles). A single fraction of 20Gy SABR was administered to 1-2 disease sites within five days prior to first and second doses of avelumab. Primary endpoint was disease control rate (DCR); secondary endpoints were PSA response (PSA 50 ), overall response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS) and safety. Radiographic disease assessment (CT and bone scintigraphy) was performed after cycles 6 and 12 of avelumab treatment. Following enrolment of 14 pts, a protocol amendment allowed avelumab beyond 12 cycles in pts with disease control at 24 weeks. Results: Thirty-one pts were enrolled, with 30 evaluable for the primary endpoint. Median follow-up was 18 months (mo). Pt characteristics: median age 71 years (IQR 64-75), bone-only disease 42%, visceral disease 16%, prior taxane chemotherapy 84%, treatment with both abiraterone and enzalutamide 13%. Seventy metastatic sites received SABR, most frequently to bone (90%) and soft tissue (29%) disease. Avelumab was given as second-line, third-line and fourth- or greater line systemic therapy in 29%, 42% and 29% of pts, respectively. Median cycles of avelumab administered was 9 (IQR 5-13). DCR (95% CI) was 50% (31-69) and 60% (32-84) in all-comers and soft tissue disease subgroup, respectively. Following protocol amendment, 7/17 pts (41%) received avelumab beyond 12 cycles. Incidence of grade 3-4 treatment-related AEs was 16% (no grade 5 events), with three pts requiring oral/IV corticosteroid therapy. Conclusions: Avelumab with SABR demonstrated durable disease control in treatment-refractory mCRPC with an acceptable toxicity profile. This combination warrants further investigation. Clinical trial information: ACTRN12618000954224. [Table: see text]
Correlations between Patient-Reported Outcomes and Self-Reported Characteristics in Adults with Hemophilia B and Caregivers of Children with Hemophilia B: Analysis of the Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) Study
Authors: Tyler W. Buckner, Robert Sidonio, Michelle Witkop, Christine Guelcher, Susan Cutter, Wendy E. Owens, Dawn Rotellini, Neeraj Iyer, David L Cooper
Journal: Blood (2017)
19O Preliminary safety, antitumor activity and pharmacodynamics results of HIT-IT MEDI1191 (mRNA IL-12) in patients with advanced solid tumours and superficial lesions
Authors: O. Hamid, M. Hellman, B. Carneiro, T. Marron, V. Subbiah, I. Mehmi, J. Eyles, V. Dubois, B. Ridgway, O. Hamid, A. Gasco Hernandez
Journal: Annals of Oncology (2021)
Grail’s reply to editorial on “liquid biopsy” for cancer screening
Authors: Harpal Kumar
Journal: BMJ (2021)

I write in response to some of the key points raised in Barclay and Bradley’s editorial regarding the partnership between Grail and NHS England.1

Grail’s multi-cancer early detection (MCED) test represents one of the first examples of an innovation developed by a private company but intended for public health uptake. Adding MCED to ongoing single cancer screening could dramatically improve …
Trends in the biological functions and medical applications of extracellular vesicles and analogues
Authors: Yan Zhao, Xiaolu Li, Wenbo Zhang, Lanlan Yu, Yang Wang, Zhun Deng, Mingwei Liu, Shanshan Mo, Ruonan Wang, Jinming Zhao, Shuli Liu, Yun Hao, Xiangdong Wang, Tianjiao Ji, Luo Zhang, Chenxuan Wang
Journal: Acta Pharmaceutica Sinica B (2021)

Natural extracellular vesicles (EVs) play important roles in many life processes such as in the intermolecular transfer of substances and genetic information exchanges. Investigating the origins and working mechanisms of natural EVs may provide an understanding of life activities, especially regarding the occurrence and development of diseases. Additionally, due to their vesicular structure, EVs (in small molecules, nucleic acids, proteins, etc.) could act as efficient drug-delivery carriers. Herein, we describe the sources and biological functions of various EVs, summarize the roles of EVs in disease diagnosis and treatment, and review the application of EVs as drug-delivery carriers. We also assess the challenges and perspectives of EVs in biomedical applications.
Radiologist faces second tribunal after High Court quashes 12 month suspension
Authors: Clare Dyer
Journal: BMJ (2021)

A High Court judge has quashed a sanction of 12 months suspension from the UK medical register for a doctor who breached conditions banning him from working as a consultant, after the General Medical Council argued that the punishment was too light.1

Anthony Donadio, who was working as a locum consultant radiologist in London, was referred to the GMC by his clinical director after a high rate of false positives in radiology results was noted by several clinical departments. As a result, patients were needlessly worried about the prospect of having cancer and were subjected to unnecessary tests and scans, the court was told.

Donadio underwent a GMC performance assessment, which found his performance deficient and recommended that he should work only at the level of a supervised junior …