tbuckley/cabot-search huggingface dataset:
A phase I/II dose-escalation study of fractionated and multiple dose 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC).
Authors: Michael Sun, Jones T. Nauseef, Justin M Lebenthal, Muhammad Junaid Niaz, Sharon Singh, Tessa A Chamberlain, Mahelia Bissassar, Amie Patel, Angela Tan, Shankar Vallabhajosula, John Babich, Paul J. Christos, Joseph Osborne, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Neil Harrison Bander, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2021)

TPS188 Background: Prostate-specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT) is a promising treatment. PSMA-targeting via large antibodies vs small molecules has different kinetics, biodistribution, and resulting clinical toxicities. Using beta-TRT, 177Lu-J591 has more heme toxicity and 177Lu-PSMA-617 more non-heme toxicity (xerostomia and nausea) [Niaz AUA 2020]. Alpha-emitters are more potent than beta radionuclides, and alpha-PSMA-TRT has efficacy even after beta-PSMA-TRT. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg [Tagawa ASCO 2020]. No maximal tolerated dose (MTD) was achieved. One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of grade 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had grade &gt; 3 heme toxicity or grade &gt; 2 non-heme toxicity. Preliminary results indicate 64% had any PSA decline and 41% had &gt; 50% PSA decline (PSA50) across all doses, despite lack of selection for PSMA expression and the majority having been previously treated with 177Lu-PSMA. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function (including normal neutrophil and platelet counts), and prior receipt of AR pathway inhibitor and chemotherapy (or refuse/ineligible for chemotherapy). There is no limit to prior lines of therapy except alpha-PSMA-TRT. Phase I includes 2 separate parallel dose-escalation cohorts. In the fractionated-dose cohort, men will receive a single cycle of 225Ac-J591 administered on D1 and D15. In the multiple-dose cohort, 225Ac-J591 will be given every 6 weeks for up to 4 cycles. The phase I component is a 3+3 dose-escalation study design, with the goal of identifying MTD. Each phase II component will treat up to 27 men with PSMA+ PET scans in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup, but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment began in August 2020 (NCT04506567). Clinical trial information: NCT04506567.
Evolutionary Dynamics of the OR Gene Repertoire in Teleost Fishes: Evidence of an Association with Changes in Olfactory Epithelium Shape
Authors: Maxime Policarpo, Katherine E Bemis, James C Tyler, Cushla J Metcalfe, Patrick Laurenti, Jean-Christophe Sandoz, Sylvie Rétaux, Didier Casane
Journal: Molecular Biology and Evolution (2021)

Abstract Teleost fishes perceive their environment through a range of sensory modalities, among which olfaction often plays an important role. Richness of the olfactory repertoire depends on the diversity of receptors coded by homologous genes classified into four families: OR, TAAR, VR1, and VR2. Herein, we focus on the OR gene repertoire. While independent large contractions of the OR gene repertoire associated with ecological transitions have been found in mammals, little is known about the diversity of the OR gene repertoire and its evolution in teleost fishes, a group that includes more than 34,000 living species. We analyzed genomes of 163 species representing diversity in this large group. We found a large range of variation in the number of functional OR genes, from 15 in the Broad-nose Pipefish Syngnathus typhle and the Ocean Sunfish Mola mola, to 429 in the Zig-zag Eel Mastacembelus armatus. The number of OR genes was higher in species when a multilamellar olfactory rosette was present. Moreover, the number of lamellae was correlated with the richness of the OR gene repertoire. While a slow and balanced birth-and-death process generally drives the evolution of the OR gene repertoire, we inferred several episodes of high rates of gene loss, sometimes followed by large gains in the number of OR genes. These gains coincide with morphological changes of the olfactory organ and suggest a strong functional association between changes in the morphology and the evolution of the OR gene repertoire.
Early surrogate measures for ablative therapies for intermediate-risk prostate cancer patients.
Authors: Rachel Glicksman, Amar Upadhyaya Kishan, Alan W. Katz, Constantine Anastasios Mantz, Sean P. Collins, Donald B. Fuller, Liying Zhang, Andrew Loblaw
Journal: Journal of Clinical Oncology (2021)

241 Background: Stereotactic body radiotherapy (SBRT) is increasingly used to treat patients with intermediate-risk prostate cancer (IR-PCa), but there is a lack of early surrogate measures in this patient population treated with SBRT to guide clinicians and patients. We aim to explore the outcomes of IR-PCa patients treated with SBRT and to assess the role of PSA response at 4 years (4yPSARR) as an early surrogate measure given its encouraging results in patients treated with brachytherapy. Methods: Individual patient data from 6 institutions for 820 patients with IR-PCa treated with SBRT between 2006 and 2014 were analyzed. Cumulative incidence of biochemical recurrence (defined by Phoenix criteria) was calculated using Nelson-Aalen estimates, and metastases-free survival and overall survival were calculated using the Kaplan-Meier method. Biochemical recurrence-free survival was analyzed according to 4yPSARR with groups dichotomized based on PSA &lt; 0.4 ng/mL or &gt;0.4 ng/mL and compared using Log-rank test. Results: 820 patients were included, including 549 (67%) with favorable intermediate and 271 (33%) with unfavorable intermediate risk disease defined by NCCN risk group classification. Median age at time of treatment was 70 years. The most common dose, fractionation and treatment schedule was 36.25 Gy in 5 fractions prescribed to the planning target volume delivered every other day. Androgen deprivation therapy was used in combination with SBRT in 9.2% of patients for a median duration of 3 months. Median follow-up was 5.9 years. The cumulative incidence of biochemical recurrence was 7.9% at 5 years. Metastases-free survival and overall survival rates at 5 years were 99.4% and 94.6%, respectively. Median 4yPSARR (n = 504) was 0.2 ng/mL. Biochemical recurrence-free survival in patients with 4yPSARR &lt; 0.4 ng/mL (n = 387) was 99.2%, and in patients with 4yPSARR &gt;0.4 ng/mL (n = 117) was 81.5% at 5 years (p &lt; 0.0001). Conclusions: Prostate SBRT is an effective treatment modality in men with IR-PCa with at least comparable rates of biochemical failure and metastases compared to other standard treatment modalities in patients with IR-PCa. 4yPSARR may represent an early surrogate measure for use in this patient population treated with SBRT and should be included for further study in prospective SBRT trials.
36MO Safety, tolerability and preliminary efficacy of poziotinib with twice daily strategy in EGFR/HER2 Exon 20 mutant non-small cell lung cancer
Authors: A. Sacher, X. Le, R. Cornelissen, E. Shum, J. Suga, M. Socinski, J.R. Molina, E. Haura, J. Clarke, G. Bhat, F. Lebel, M.C. Garassino
Journal: Annals of Oncology (2021)
Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia with Monosomy 7 or Deletion 7q: A Study from the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT)
Authors: Xavier Poire, Myriam Labopin, Emmanuelle Polge, Liisa Volin, Jürgen Finke, Arnold Ganser, Didier Blaise, Ibrahim Yakoub-Agha, Dietrich W Beelen, Noel Milpied, Marie-Pierre Ledoux, Gérard Socié, Dietger Niederwieser, Mauricette Michallet, Johan Maertens, Jan J Cornelissen, Charles Craddock, Mohamad Mohty, Jordi Esteve, Arnon Nagler
Journal: Blood (2017)
Evaluation of Selective Survival and Sex/Gender Differences in Dementia Incidence Using a Simulation Model
Authors: Crystal Shaw, Eleanor Hayes-Larson, M. Maria Glymour, Carole Dufouil, Timothy J. Hohman, Rachel A. Whitmer, Lindsay C. Kobayashi, Ron Brookmeyer, Elizabeth Rose Mayeda
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Dementia research is susceptible to bias arising from selective survival, a process that results in individuals with certain characteristics disproportionately surviving to old age. Spurious associations between risk factors and dementia may be induced when factors associated with longer survival also influence dementia incidence. <h3>Objective</h3> To assess the role of selective survival in explaining reported sex/gender differences in dementia incidence. <h3>Design, Setting, and Participants</h3> This decision analytical model used a simulated cohort of US participants aged 50 years and without dementia at baseline followed up for incident dementia through age 95 years. Selective survival was induced by a selection characteristic (eg, childhood social disadvantage or Alzheimer genetic risk) that influenced both mortality and dementia incidence at varying magnitudes. Data analysis was performed from April 2018 to May 2020. <h3>Exposure</h3> Sex/gender, conceptualized as the combination of biological sex and social consequences of gender. <h3>Main Outcomes and Measures</h3> Dementia incidence rate ratios (IRRs) for women compared with men. In all simulations, it was assumed that there would be no true effect of sex/gender on dementia incidence; all observed sex/gender differences were due to selective survival. <h3>Results</h3> At baseline, the simulation included 100 000 participants aged 50 years (51 000 [51%] women, mirroring the 1919-1921 US birth cohort of non-Latino White individuals at age 50 years); distributions of the selection characteristic were standard normal (mean [SD], 0.0 [1.0]). Observed sex/gender differences in dementia incidence in individuals aged 85 years or older ranged from insignificant (IRR, 1.00; 95% CI, 0.91-1.11) to consistent with sex/gender differences (20% higher risk for women [IRR, 1.20; 95% CI, 1.08-1.32]) reported in an extant study. Simulations in which bias was large enough to explain prior findings required moderate to large differential effects of selective survival (eg, hazard ratio for selection characteristic on mortality at least 2.0 among men, no effect among women). <h3>Conclusions and Relevance</h3> These results suggest that selective survival may contribute to observed sex/gender differences in dementia incidence but do not preclude potential contributions of sex/gender-specific mechanisms. Further research on plausibility of selection characteristics with outcomes of the magnitude required for selective survival to explain sex/gender differences in dementia incidence and sex/gender-specific mechanisms represent an opportunity to understand prevention and treatment of dementia.
COVID-19 vaccines for patients with cancer: benefits likely outweigh risks
Authors: Joyce K. Hwang, Tian Zhang, Andrew Z. Wang, Zihai Li
Journal: Journal of Hematology & Oncology (2021)

Less than a year since the start of the COVID-19 pandemic, ten vaccines against SARS-CoV-2 have been approved for at least limited use, with over sixty others in clinical trials. This swift achievement has generated excitement and arrives at a time of great need, as the number of COVID-19 cases worldwide continues to rapidly increase. Two vaccines are currently approved for full use, both built on mRNA and lipid nanotechnology platforms, a success story of mRNA technology 20 years in the making. For patients with cancer, questions arise around the safety and efficacy of these vaccines in the setting of immune alterations engendered by their malignancy and/or therapies. We summarize the current data on leading COVID-19 vaccine candidates and vaccination of patients undergoing immunomodulatory cancer treatments. Most current cancer therapeutics should not prevent the generation of protective immunity. We call for more research in this area and recommend that the majority of patients with cancer receive COVID vaccinations when possible.
Plasma-Signature-Model for End-Stage Liver Disease Score to Predict Survival in Severe Alcoholic Hepatitis
Authors: Naoto Fujiwara, Eric Trépo, Indu Raman, Quan-Zhen Li, Delphine Degré, Thierry Gustot, Christophe Moreno, Yujin Hoshida
Journal: Clinical Gastroenterology and Hepatology (2021)
Abstract 14899: Personalized Computational Modeling Identifies Embolic Stroke of Undetermined Source Patients With Potential Arrhythmic Substrate
Authors: Savannah Bifulco, Griffin D Scott, Sakher Sarairah, Zeinab Birjandian, Caroline Roney, Steven A Niederer, Christian Mahnkopf, Peter Kuhnlein, Marcel Mitlacher, David Tirschwell, Nazem W Akoum, Patrick M Boyle
Journal: Circulation (2020)

Introduction: Late-gadolinium enhanced (LGE)-MRI has revealed atrial fibrotic remodeling in embolic stroke of undetermined source (ESUS) patients. Curiously, fibrosis levels in ESUS patients are the same as those observed in AF. A potential explanation is that ESUS patients have pre-clinical arrhythmic substrate, but lack the triggers needed to initiate AF. Hypothesis: Simulations in computational models reconstructed from LGE-MRI scans can determine if the fibrotic substrate of a particular ESUS patient has the capacity to sustain reentry. Methods: ESUS (per standard criteria) was verified by a neurologist. 45 ablation-naïve AF patients and 45 ESUS patients within three months of stroke underwent LGE-MRI for fibrosis assessment. Left atrial (LA) models were built from LGE-MRI scans. Fiber orientations were mapped into each LA model using universal atrial coordinates. Burst pacing from 15 sites was used to test inducibility of arrhythmia sustained by reentry (Fig A). Results: In 23/45 (51%) ESUS and 29/45 (64%) AF models, we observed sustained reentry. Fibrosis burden was significantly higher for patients in whom simulations suggested the existence of pre-clinical arrhythmic substrate; however, within the inducible and non-inducible sub-groups, there was no significant difference in fibrosis burden for ESUS vs. AF patients (Fig B). This suggests that the presence of pre-clinical substrate in ESUS is correlated with fibrosis burden, although exceptions to this supposition were not uncommon (i.e., inducible low-fibrosis and non-inducible high-fibrosis models; Fig C). Conclusions: In this modeling study, pro-arrhythmic properties of fibrosis in ESUS and AF are indistinguishable. This suggests that some ESUS patients have pre-clinical fibrotic substrate, but do not have AF due to a lack of suitable triggers. Ongoing clinical follow-up will test whether abundance of pre-clinical substrate is predictive of incident AF.
Immunoregulatory and lipid presentation pathways are upregulated in human face transplant rejection
Authors: Thet Su Win, William J. Crisler, Beatrice Dyring-Andersen, Rachel Lopdrup, Jessica E. Teague, Qian Zhan, Victor Barrera, Shannan Ho Sui, Sotirios Tasigiorgos, Naoka Murakami, Anil Chandraker, Stefan G. Tullius, Bohdan Pomahac, Leonardo V. Riella, Rachael A. Clark
Journal: Journal of Clinical Investigation (2021)

BACKGROUNDRejection is the primary barrier to broader implementation of vascularized composite allografts (VCAs), including face and limb transplants. The immunologic pathways activated in face transplant rejection have not been fully characterized.METHODSUsing skin biopsies prospectively collected over 9 years from 7 face transplant patients, we studied rejection by gene expression profiling, histology, immunostaining, and T cell receptor sequencing.RESULTSGrade 1 rejection did not differ significantly from nonrejection, suggesting that it does not represent a pathologic state. In grade 2, there was a balanced upregulation of both proinflammatory T cell activation pathways and antiinflammatory checkpoint and immunomodulatory pathways, with a net result of no tissue injury. In grade 3, IFN-γ-driven inflammation, antigen-presenting cell activation, and infiltration of the skin by proliferative T cells bearing markers of antigen-specific activation and cytotoxicity tipped the balance toward tissue injury. Rejection of VCAs and solid organ transplants had both distinct and common features. VCA rejection was uniquely associated with upregulation of immunoregulatory genes, including SOCS1; induction of lipid antigen-presenting CD1 proteins; and infiltration by T cells predicted to recognize CD1b and CD1c.CONCLUSIONOur findings suggest that the distinct features of VCA rejection reflect the unique immunobiology of skin and that enhancing cutaneous immunoregulatory networks may be a useful strategy in combatting rejection.Trial registrationClinicalTrials.gov NCT01281267.FUNDINGAssistant Secretary of Defense and Health Affairs, through Reconstructive Transplant Research (W81XWH-17-1-0278, W81XWH-16-1-0647, W81XWH-16-1-0689, W81XWH-18-1-0784, W81XWH-1-810798); American Society of Transplantation's Transplantation and Immunology Research Network Fellowship Research Grant; Plastic Surgery Foundation Fellowship from the American Society of Plastic Surgeons; Novo Nordisk Foundation (NNF15OC0014092); Lundbeck Foundation; Aage Bangs Foundation; A.P. Moller Foundation for the Advancement of Medical Science; NIH UL1 RR025758.
Molecular bases for the association of FHR-1 with atypical hemolytic uremic syndrome and other diseases
Authors: Héctor Martin Merinero, Marta Subías, Amaia Pereda, Elena Gómez-Rubio, Lucia Juana Lopez, Constantino Fernandez, Elena Goicoechea de Jorge, Sonsoles Martin-Santamaria, Francisco Javier Cañada, Santiago Rodríguez de Córdoba
Journal: Blood (2021)
Enfortumab vedotin in FGFR3-mutated advanced urothelial carcinoma.
Authors: Min Yuen Teo, Neha Ratna, Ashley Marie Regazzi, Danielle Elise Zimmerman, Deaglan Joseph McHugh, Andrew Leonard Laccetti, Han Xiao, Chung-Han Lee, David Henry Aggen, Samuel Aaron Funt, Dean F. Bajorin, Gopa Iyer, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2021)

458 Background: Enfortumab vedotin (EV) and, for those with FGFR3 mutations (FGFR3+), erdafitinib, are established therapeutic options for refractory advanced urothelial carcinoma. However, optimal sequencing of these agents remains undefined. Here, we report our experience of EV monotherapy with focus on patients (pts) with FGFR3 alterations. Methods: Pts who were treated with EV were identified. Clinical data and outcomes were extracted. Tumor genomic profiles by the MSK-IMPACT assay as part of standard of care were reviewed for FGFR3 and other commonly altered gene mutations and tumor mutation burden (TMB). Progression-free (PFS) and overall survival (OS) were measured from start of EV therapy and compared with unadjusted log-rank test. Results: 89 patients received EV on completed monotherapy studies (n = 37) or as standard of care. Median age was 62 years (IQR: 62 – 78), 71% were male (n = 63), 28% had liver metastases. Distribution per Bellmunt score (0 – 3) was: 12%, 42%, 37% and 9%. For the entire population, PFS and OS were 5.2 and 11.4 months, respectively, with response rate of 52% among 75 evaluable patients. MSK-IMPACT was available for 80 patients. Overall genomic profile was similar to TCGA cohort except for fewer DNA damage response/repair gene alterations – 15% (ERCC2: 2; ATM: 4, BRCA1: 2, BRCA2: 3, RAD51C: 1) and FGFR3+ rate of 33%. Median TMB was 8.9/Mb (IQR: 5.2 – 13.3). Of the 26 FGFR3+ pts, 8 and 1 received an FGFR3 inhibitor (FGFR3i) before and after EV, respectively. 17 pts have not been exposed to FGFR3i; 13 of whom have progressed on EV and 9 died. Compared to FGFR3- pts, FGFR3+ pts with no prior FGFRi had significantly shorter median PFS on EV (2.5 vs. 6.8 months; HR 0.33 [0.14 – 0.80] p &lt; .01) and trend towards shorter median OS (4.9 vs. 14.6 months; HR 0.42 [0.16 – 1.08] p &gt; .05). PFS on EV among FGFR3+ pts with prior FGFR3i exposure was 6.7 months, similar to FGFR3- pts (HR 0.77 [0.30 – 1.96] p = .6). Response rates for FGFR3+ with and without prior FGFRi, and FGFR3- pts on EV were 4/7 (50%), 5/13 (38%) and 29/48 (60%). Conclusions: In this retrospective study, FGFR+ patients who receive EV first appear to have shorter PFS and lower ORR than those who have received prior FGFRi. Prospective studies on the sequence of EV and FGFR3i in FGFR3+ pts are warranted.
Oral dimethyl fumarate induces changes within the peripheral neutrophil compartment of patients with psoriasis that are linked with skin improvement*
Authors: P.J. Morrison, I. Suhrkamp, S. Gerdes, U. Mrowietz
Journal: British Journal of Dermatology (2021)

Dimethyl fumarate (DMF) is a treatment for moderate-to-severe psoriasis and multiple sclerosis. DMF therapy typically improves skin inflammation within the first 3 months of treatment. DMF is a prodrug that generates the hydroxycarboxylic acid receptor 2 (HCA2) agonist, monomethyl fumarate (MMF). Despite widespread clinical use, DMF's mechanism of action is not fully understood.We wished to characterize the changes induced by DMF in peripheral neutrophils within the first 3 months of treatment to better understand its early antipsoriatic effects.Flow cytometry was used to assess T-cell and neutrophil frequencies, apoptosis and activation phenotype. In vitro culture of neutrophils with DMF and MMF was used to evaluate apoptosis and HCA2 internalization. Serum levels of neutrophil degranulation products were measured by enzyme-linked immunosorbent assay.Patients with psoriasis had significantly higher leucocyte counts at baseline compared with controls, with a large population of pro-inflammatory CD62Llo CD11bbright neutrophils. Analysis revealed that DMF treatment reduced the frequency of CD62Llo CD11bbright neutrophils and serum levels of neutrophil activation markers. This reduction was not linked to increased apoptosis.Our results reveal a novel in vivo effect of DMF therapy on pro-inflammatory neutrophils that likely contributes to this treatment's antipsoriatic efficacy.