tbuckley/cabot-search huggingface dataset:
Combining Targeted Radionuclide Therapy and Immune Checkpoint Inhibition for Cancer Treatment
Authors: Simone C. Kleinendorst, Egbert Oosterwijk, Johan Bussink, Harm Westdorp, Mark W. Konijnenberg, Sandra Heskamp
Journal: Clinical Cancer Research (2022)

Abstract The development of immunotherapy, in particular immune checkpoint inhibitors (ICI), has revolutionized cancer treatment in the past decades. However, its efficacy is still limited to subgroups of patients with cancer. Therefore, effective treatment combination strategies are needed. Here, radiotherapy is highly promising, as it can induce immunogenic cell death, triggering the release of pro-inflammatory cytokines, thereby creating an immunogenic phenotype and sensitizing tumors to ICI. Recently, targeted radionuclide therapy (TRT) has attained significant interest for cancer treatment. In this approach, a tumor-targeting radiopharmaceutical is used to specifically deliver a therapeutic radiation dose to all tumor cells, including distant metastatic lesions, while limiting radiation exposure to healthy tissue. However, fundamental differences between TRT and conventional radiotherapy make it impossible to directly extrapolate the biological effects from conventional radiotherapy to TRT. In this review, we present a comprehensive overview of studies investigating the immunomodulatory effects of TRT and the efficacy of combined TRT-ICI treatment. Preclinical studies have evaluated a variety of murine cancer models in which α- or β-emitting radionuclides were directed to a diverse set of targets. In addition, clinical trials are ongoing to assess safety and efficacy of combined TRT-ICI in patients with cancer. Taken together, research indicates that combining TRT and ICI might improve therapeutic response in patients with cancer. Future research has to disclose what the optimal conditions are in terms of dose and treatment schedule to maximize the efficacy of this combined approach.
Bacillus Calmette-Guérin vaccine to reduce healthcare worker absenteeism in COVID-19 pandemic, a randomized controlled trial
Authors: Thijs ten Doesschate, Thomas W. van der Vaart, Priya A. Debisarun, Esther Taks, Simone J.C.F.M. Moorlag, Nienke Paternotte, Wim G. Boersma, Vincent P. Kuiper, Anna H.E. Roukens, Bart J.A. Rijnders, Andreas Voss, Karin M. Veerman, Angele P.M. Kerckhoffs, Jaap ten Oever, Reinout van Crevel, Cees van Nieuwkoop, Arief Lalmohamed, Janneke H.H.M. van de Wijgert, Mihai G. Netea, Marc J.M. Bonten, Cornelis H. van Werkhoven
Journal: Clinical Microbiology and Infection (2022)

Objectives: The COVID-19 pandemic increases healthcare worker (HCW) absenteeism.The bacillus Calmette-Gu erin (BCG) vaccine may provide non-specific protection against respiratory infections through enhancement of trained immunity.We investigated the impact of BCG vaccination on HCW absenteeism during the COVID-19 pandemic.Methods: HCWs exposed to COVID-19 patients in nine Dutch hospitals were randomized to BCG vaccine or placebo in a 1:1 ratio, and followed for one year using a mobile phone application.The primary endpoint was the self-reported number of days of unplanned absenteeism for any reason.Secondary endpoints included documented COVID-19, acute respiratory symptoms or fever.This was an investigator-funded study, registered at ClinicalTrials.gov(NCT03987919).Results: In March/April 2020, 1511 HCWs were enrolled.The median duration of follow-up was 357 person-days (interquartile range [IQR], 351 to 361).Unplanned absenteeism for any reason was observed in 2.8% of planned working days in the BCG group and 2.7% in the placebo group (adjusted relative risk 0.94; 95% credible interval, 0.78e1.15).Cumulative incidences of documented COVID-19 were 14.2% in the BCG and 15.2% in the placebo group (adjusted hazard ratio (aHR) 0.94; 95% confidence interval (CI), 0.72e1.24).First episodes of self-reported acute respiratory symptoms or fever occurred in 490 (66.2%)
The 2021 Global Lung Cancer Therapy Landscape
Authors: Dhruba Deb, Amy C. Moore, Upal Basu Roy
Journal: Journal of Thoracic Oncology (2022)

The lung cancer treatment landscape has substantially evolved over the past decade. However, a systematic analysis of the current global drug development landscape has not been conducted.We curated and analyzed a comprehensive list of therapeutic entities (TEs) in preclinical development and clinical trials for lung cancer.On the basis of our analysis of 707 TEs, we found a consistent forward trajectory in the development pipeline for both NSCLC and SCLC. Most of the TEs were in the advanced stages of clinical trials. Targeted therapies continue to dominate in the non-immuno-oncology space. Immuno-oncology targets are expanding beyond inhibitors of the programmed death-ligand 1 axis.Our analysis highlights a robust portfolio of both preclinical and clinical TEs and suggests that lung cancer treatment is going to become even more biomarker-driven.
Diagnosis and management of covid-19 in pregnancy
Authors: Melanie Nana, Kenneth Hodson, Nuala Lucas, Luigi Camporota, Marian Knight, Cathy Nelson-Piercy
Journal: BMJ (2022)

Abstract Pregnant women with covid-19 are at greater risk of severe disease than their non-pregnant peers, and yet they are frequently denied investigations or treatments because of unfounded concerns about risk to the fetus. The basic principles of diagnosing and managing covid-19 are the same as for non-pregnant patients, and a multidisciplinary, expert team approach is essential to ensure optimal care. During pregnancy, treatment with corticosteroids should be modified to use non-fluorinated glucocorticoids. Il-6 inhibitors and monoclonal antibodies, together with specific antiviral therapies, may also be considered. Prophylaxis against venous thromboembolism is important. Women may require respiratory support with oxygen, non-invasive ventilation, ventilation in a prone position (either awake or during invasive ventilation), intubation and ventilation, and extracorporeal membrane oxygenation (ECMO). Pregnancy is not a contraindication for any of these supportive therapies, and the criteria for providing them are the same as in the general population. Decisions regarding timing, place, and mode of delivery should be taken with a multidisciplinary team including obstetricians, physicians, anesthetists, and intensivists experienced in the care of covid-19 in pregnancy. Ideally these decisions should take place in consultation with centers that have experience and expertise in all these specialties.
Health and development from preconception to 20 years of age and human capital
Authors: Robert E Black, Li Liu, Fernando P Hartwig, Francisco Villavicencio, Andrea Rodriguez-Martinez, Luis P Vidaletti, Jamie Perin, Maureen M Black, Hannah Blencowe, Danzhen You, Lucia Hug, Bruno Masquelier, Simon Cousens, Amber Gove, Tyler Vaivada, Diana Yeung, Jere Behrman, Reynaldo Martorell, Clive Osmond, Aryeh D Stein, Linda S Adair, Caroline H D Fall, Bernardo Horta, Ana M B Menezes, Manuel Ramirez-Zea, Linda M Richter, George C Patton, Eran Bendavid, Majid Ezzati, Zulfiqar A Bhutta, Joy E Lawn, Cesar G Victora
Journal: The Lancet (2022)
Author Correction: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility
Authors: Julien Barc, Rafik Tadros, Charlotte Glinge, David Y. Chiang, Mariam Jouni, Floriane Simonet, Sean J. Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A. Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O. Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D. Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F. Giachino, Natascia Cerrato, Raphaël P. Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K. Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P. Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B. Shoemaker, Bas J. Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, Konstantin Strauch, Annette Peters, Holger Schulz, Lars Schwettmann, Reiner Leidl, Margit Heier, Jan H. Veldink, Leonard H. van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E. Odening, Marina Cerrone, Larry A. Chinitz, Paul G. Volders, Maarten P. van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D. Roberts, Laurence Jesel, Martin Borggrefe, Pier D. Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G. Priori, Carlo Napolitano, Pascal Defaye, Frédéric Anselme, Jean Philippe Darmon, François Wiart, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R. Gimeno, Can Hasdemir, Peter J. Schwartz, Lia Crotti, Pascal P. McKeown, Sanjay Sharma, Elijah R. Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L. Tan, Carol A. Remme, Pieter G. Postema, Mario Delmar, Patrick T. Ellinor, Steven A. Lubitz, Jean-Baptiste Gourraud, Michael W. Tanck, Alfred L. George, Calum A. MacRae, Paul W. Burridge, Christian Dina, Vincent Probst, Arthur A. Wilde, Jean-Jacques Schott, Richard Redon, Connie R. Bezzina
Journal: Nature Genetics (2022)
Factors correlating with survival following adjuvant or definitive radiosurgery for large brain metastases
Authors: Enrique Gutiérrez-Valencia, Aristotelis Kalyvas, Conrad J Villafuerte, Barbara-Ann Millar, Normand Laperriere, Tatiana Conrad, Alejandro Berlin, Jessica Weiss, Gelareh Zadeh, Mark Bernstein, Paul Kongkham, David B Shultz
Journal: Neuro-Oncology (2022)

We sought to identify variates correlating with overall survival (OS) in patients treated with surgery (S) plus adjuvant stereotactic radiosurgery (SRS) versus definitive SRS for large (&gt;4 cc) brain metastases (BrM).We used univariate (UVA) and multivariate analyses (MVA) to identify survival correlates among eligible patients identified from a prospective registry and compared definitive SRS to S+ adjuvant SRS cohorts using propensity score-matched analysis (PSMA). Secondary outcomes were measured using the cumulative incidence (CI) method.We identified 364 patients; 127 and 237 were treated with S+SRS and definitive SRS, respectively. On UVA, SRS alone [HR1.73 (1.35,2.22) P &lt; .001), BrM quantity [HR 1.13 (1.06-1.22) (P &lt; .001)]; performance status (PS) [HR 2.78 (1.73-4.46) (P &lt; .001)]; extracranial disease (ECD) [HR 1.82 (1.37,2.40) (P &lt; .001)]; and receipt of systemic treatment after BrM therapy, [HR 0.58 (0.46-073) (P &lt; .001)] correlated with OS. On MVA, SRS alone [HR 1.81 (1.19,2.74) (P &lt; .0054)], SRS target volume [HR 1.03 (1.01,1.06) (P &lt; .0042)], and receipt of systemic treatment [HR 0.68 (0.50,0.93) (P &lt; .015)] correlated with OS. When PSMA was used to balance ECD, BrM quantity, PS, and SRS target volume, SRS alone remained correlated with worsened OS [HR 1.62 (1.20-2.19) (P = 0.0015)]. CI of local failure requiring resection at 12 months was 3% versus 7% for S+SRS and SRS cohorts, respectively [(HR 2.04 (0.89-4.69) (P = .091)]. CI of pachymeningeal failure at 12 months was 16% versus 0% for S+SRS and SRS.SRS target volume, receipt of systemic therapies, and treatment with S+SRS instead of definitive SRS correlated with improved survival in patients with large BrM.
Assessment of Proton Beam Therapy Use Among Patients With Newly Diagnosed Cancer in the US, 2004-2018
Authors: Leticia M. Nogueira, Ahmedin Jemal, K. Robin Yabroff, Jason A. Efstathiou
Journal: JAMA Network Open (2022)

Proton beam therapy (PBT) is a potentially superior technology to photon radiotherapy for tumors with complex anatomy, those surrounded by sensitive tissues, and childhood cancers.To assess patterns of use of PBT according to the present American Society of Radiation Oncology (ASTRO) clinical indications in the US.Individuals newly diagnosed with cancer between 2004 and 2018 were selected from the National Cancer Database. Data analysis was performed from October 4, 2021, to February 22, 2022. ASTRO's Model Policies (2017) were used to classify patients into group 1, for which health insurance coverage for PBT treatment is recommended, and group 2, for which coverage is recommended only if additional requirements are met.Use of PBT.Of the 5 919 368 patients eligible to receive PBT included in the study, 3 206 902 were female (54.2%), and mean (SD) age at diagnosis was 62.6 (12.3) years. Use of PBT in the US increased from 0.4% in 2004 to 1.2% in 2018 (annual percent change [APC], 8.12%; P < .001) due to increases in group 1 from 0.4% in 2010 to 2.2% in 2018 (APC, 21.97; P < .001) and increases in group 2 from 0.03% in 2014 to 0.1% in 2018 (APC, 30.57; P < .001). From 2010 to 2018, among patients in group 2, PBT targeted to the breast increased from 0.0% to 0.9% (APC, 51.95%), and PBT targeted to the lung increased from 0.1% to 0.7% (APC, 28.06%) (P < .001 for both). Use of PBT targeted to the prostate decreased from 1.4% in 2011 to 0.8% in 2014 (APC, -16.48%; P = .03) then increased to 1.3% in 2018 (APC, 12.45; P < .001). Most patients in group 1 treated with PBT had private insurance coverage in 2018 (1039 [55.4%]); Medicare was the most common insurance type among those in group 2 (1973 [52.5%]).The findings of this study show an increase in the use of PBT in the US between 2004 to 2018; prostate was the only cancer site for which PBT use decreased temporarily between 2011 and 2014, increasing again between 2014 and 2018. These findings may be especially relevant for Medicare radiation oncology coverage policies.
Laser ablation: Heating up the anti-tumor response in the intracranial compartment
Authors: Emily C. Lerner, Ryan M. Edwards, Daniel S. Wilkinson, Peter E. Fecci
Journal: Advanced Drug Delivery Reviews (2022)

Immunotherapies, such as immune checkpoint inhibition (ICI), have had limited success in treating intracranial malignancies. These failures are due partly to the restrictive blood–brain-barrier (BBB), the profound tumor-dependent induction of local and systemic immunosuppression, and immune evasion exhibited by these tumors. Therefore, novel approaches must be explored that aim to overcome these stringent barriers. LITT is an emerging treatment for brain tumors that utilizes thermal ablation to kill tumor cells. LITT provides an additional therapeutic benefit by synergizing with ICI and systemic chemotherapies to strengthen the anti-tumor immune response. This synergistic relationship involves transient disruption of the BBB and local augmentation of immune function, culminating in increased CNS drug penetrance and improved anti-tumor immunity. In this review, we will provide an overview of the challenges facing immunotherapy for brain tumors, and discuss how LITT may synergize with the endogenous anti-tumor response to improve the efficacy of ICI.
Association of COVID-19 Vaccination With Risk of COVID-19 Infection, Hospitalization, and Death in Heart Transplant Recipients
Authors: Laura L. Peters, David S. Raymer, Jay D. Pal, Amrut V. Ambardekar
Journal: JAMA Cardiology (2022)

<h3>Importance</h3> Orthotopic heart transplant (OHT) recipients are at increased risk for morbidity and mortality after SARS-CoV-2 infection. Although antibody response to COVID-19 vaccination is lower in solid organ transplant recipients, there has been no study assessing the safety and effectiveness of COVID-19 vaccination in OHT recipients. <h3>Objective</h3> To assess the safety and effectiveness of COVID-19 vaccination and associations with SARS-CoV-2 infection and clinical outcomes in a large population of adult OHT recipients. <h3>Design, Setting, and Participants</h3> This case-control study examined data from a US heart transplant program at a single center for all adult recipients of OHT who were followed up from January 15, 2021, through January 31, 2022. <h3>Main Outcomes and Measures</h3> The primary outcome was number of SARS-CoV-2 infections and related hospitalizations, intensive care unit (ICU) admissions, and deaths between vaccinated vs unvaccinated adult recipients of OHT. <h3>Results</h3> A total of 436 patients who received OHT were included in the study, of which 106 patients were infected with COVID-19. The mean (SD) age was 54 (17) years; 303 (69.5%) were men and 133 (30.5%) were women. There were 366 patients in the vaccinated cohort with 72 COVID-19 infections (19.7%), 15 hospitalizations (4.1%), 4 ICU admissions (1.1%), and 3 deaths (0.8%). There were 70 patients in the unvaccinated cohort with 34 COVID-19 infections (48.6%), 10 hospitalizations (14.3%), 3 ICU admissions (4.3%), and 3 deaths (4.3%). COVID-19 vaccination was associated with a lower risk of COVID-19 infection (risk ratio [RR], 0.41; 95% CI, 0.30-0.56), hospitalization (RR, 0.29; 95% CI, 0.14-0.61), and death (RR, 0.19; 95% CI, 0.05-0.82). Among the 366 vaccinated OHT recipients, there was no echocardiographic evidence of graft dysfunction, clinically significant rejection, or allosensitization at 6 months after they received the COVID-19 vaccine. <h3>Conclusions and Relevance</h3> Patients with OHT who are infected with SARS-CoV-2 are at greater risk of severe infection and death compared with immunocompetent individuals. COVID-19 vaccination was associated with fewer COVID-19 infections, hospitalizations, and deaths, with no heart transplant–specific adverse events. COVID-19 vaccination for all OHT recipients is of paramount importance.
Resistance Mechanisms to Anti-PD Cancer Immunotherapy
Authors: Matthew D. Vesely, Tianxiang Zhang, Lieping Chen
Journal: Annual Review of Immunology (2022)

The transformative success of antibodies targeting the PD-1 (programmed death 1)/B7-H1 (B7 homolog 1) pathway (anti-PD therapy) has revolutionized cancer treatment. However, only a fraction of patients with solid tumors and some hematopoietic malignancies respond to anti-PD therapy, and the reason for failure in other patients is less known. By dissecting the mechanisms underlying this resistance, current studies reveal that the tumor microenvironment is a major location for resistance to occur. Furthermore, the resistance mechanisms appear to be highly heterogeneous. Here, we discuss recent human cancer data identifying mechanisms of resistance to anti-PD therapy. We review evidence for immune-based resistance mechanisms such as loss of neoantigens, defects in antigen presentation and interferon signaling, immune inhibitory molecules, and exclusion of T cells. We also review the clinical evidence for emerging mechanisms of resistance to anti-PD therapy, such as alterations in metabolism, microbiota, and epigenetics. Finally, we discuss strategies to overcome anti-PD therapy resistance and emphasize the need to develop additional immunotherapies based on the concept of normalization cancer immunotherapy.
Re: Ole Jacob Nilsen, Henriette Veiby Holm, Teresa O. Ekerhult, et al. To Transect or Not Transect: Results from the Scandinavian Urethroplasty Study, A Multicentre Randomised Study of Bulbar Urethroplasty Comparing Excision and Primary Anastomosis Versus Buccal Mucosal Grafting. Eur Urol. 2022;81:375–382
Authors: Mazhar Ortac
Journal: European Urology (2022)
Concerns Over Thyroid Cancer Surgeries and Quality of Life
Authors: Peiming Sun, Heming Yang, Wenquan Niu
Journal: JAMA Surgery (2022)

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Procoagulant platelet sentinels prevent inflammatory bleeding through GPIIBIIIA and GPVI
Authors: Rainer Kaiser, Raphael Escaig, Jan Kranich, Marie-Louise Hoffknecht, Afra Anjum, Vivien Polewka, Magdalena Mader, Wenbo Hu, Larissa Belz, Christoph Gold, Anna Titova, Michael Lorenz, Kami Pekayvaz, Stefan Kääb, Florian Gaertner, Konstantin Stark, Thomas Brocker, Steffen Massberg, Leo Nicolai
Journal: Blood (2022)

Abstract Impairment of vascular integrity is a hallmark of inflammatory diseases. We recently reported that single immune-responsive platelets migrate and reposition themselves to sites of vascular injury to prevent bleeding. However, it remains unclear how single platelets preserve vascular integrity once encountering endothelial breaches. Here we demonstrate by intravital microscopy combined with genetic mouse models that procoagulant activation (PA) of single platelets and subsequent recruitment of the coagulation cascade are crucial for the prevention of inflammatory bleeding. Using a novel lactadherin-based compound, we detect phosphatidylserine (PS)-positive procoagulant platelets in the inflamed vasculature. We identify exposed collagen as the central trigger arresting platelets and initiating subsequent PA in a CypD- and TMEM16F-dependent manner both in vivo and in vitro. Platelet PA promotes binding of the prothrombinase complex to the platelet membrane, greatly enhancing thrombin activity and resulting in fibrin formation. PA of migrating platelets is initiated by costimulation via integrin αIIbβ3 (GPIIBIIIA)/Gα13-mediated outside-in signaling and glycoprotein VI signaling, leading to an above-threshold intracellular calcium release. This effectively targets the coagulation cascade to breaches of vascular integrity identified by patrolling platelets. Platelet-specific genetic loss of either CypD or TMEM16F as well as combined blockade of platelet GPIIBIIIA and glycoprotein VI reduce platelet PA in vivo and aggravate pulmonary inflammatory hemorrhage. Our findings illustrate a novel role of procoagulant platelets in the prevention of inflammatory bleeding and provide evidence that PA of patrolling platelet sentinels effectively targets and confines activation of coagulation to breaches of vascular integrity.
Expanding Accountable Care’s Reach among Medicare Beneficiaries
Authors: Douglas Jacobs, Purva Rawal, Liz Fowler, Meena Seshamani
Journal: New England Journal of Medicine (2022)

Interview with Dr. Rishi Wadhera on the inequitable effects of value-based payment programs and a new model meant to respond to equity concerns. (11:01)Download By better aligning its initiatives and policies related to accountable care organizations, CMS hopes to create pathways for payers and providers to advance high-quality, accountable care.