tbuckley/cabot-search huggingface dataset:
Long‐term prevention of hereditary angioedema attacks with lanadelumab: The HELP OLE Study
Authors: Aleena Banerji, Jonathan A. Bernstein, Douglas T. Johnston, William R. Lumry, Markus Magerl, Marcus Maurer, Inmaculada Martinez‐Saguer, Andrea Zanichelli, James Hao, Neil Inhaber, Ming Yu, Marc A. Riedl
Journal: Allergy (2021)

Abstract Background The aim was to evaluate long‐term effectiveness and safety of lanadelumab in patients ≥12 y old with hereditary angioedema (HAE) 1/2 (NCT02741596). Methods Rollover patients completing the HELP Study and continuing into HELP OLE received one lanadelumab 300 mg dose until first attack (dose‐and‐wait period), then 300 mg q2wks (regular dosing stage). Nonrollovers (newly enrolled) received lanadelumab 300 mg q2wks from day 0. Baseline attack rate for rollovers: ≥1 attack/4 weeks (based on run‐in period attack rate during HELP Study); for nonrollovers: historical attack rate ≥1 attack/12 weeks. The planned treatment period was 33 months. Results 212 patients participated (109 rollovers, 103 nonrollovers); 81.6% completed ≥30 months on study (mean [SD], 29.6 [8.2] months). Lanadelumab markedly reduced mean HAE attack rate (reduction vs baseline: 87.4% overall). Patients were attack free for a mean of 97.7% of days during treatment; 81.8% and 68.9% of patients were attack free for ≥6 and ≥12 months, respectively. Angioedema Quality‐of‐Life total and domain scores improved from day 0 to end of study. Treatment‐emergent adverse events (TEAEs) (excluding HAE attacks) were reported by 97.2% of patients; most commonly injection site pain (47.2%) and viral upper respiratory tract infection (42.0%). Treatment‐related TEAEs were reported by 54.7% of patients. Most injection site reactions resolved within 1 hour (70.2%) or 1 day (92.6%). Six (2.8%) patients discontinued due to TEAEs. No treatment‐related serious TEAEs or deaths were reported. Eleven treatment‐related TEAEs of special interest were reported by seven (3.3%) patients. Conclusion Lanadelumab demonstrated sustained efficacy and acceptable tolerability with long‐term use in HAE patients.
Metabolic landscapes in sarcomas
Authors: Richard Miallot, Franck Galland, Virginie Millet, Jean-Yves Blay, Philippe Naquet
Journal: Journal of Hematology & Oncology (2021)

Abstract Metabolic rewiring offers novel therapeutic opportunities in cancer. Until recently, there was scant information regarding soft tissue sarcomas, due to their heterogeneous tissue origin, histological definition and underlying genetic history. Novel large-scale genomic and metabolomics approaches are now helping stratify their physiopathology. In this review, we show how various genetic alterations skew activation pathways and orient metabolic rewiring in sarcomas. We provide an update on the contribution of newly described mechanisms of metabolic regulation. We underscore mechanisms that are relevant to sarcomagenesis or shared with other cancers. We then discuss how diverse metabolic landscapes condition the tumor microenvironment, anti-sarcoma immune responses and prognosis. Finally, we review current attempts to control sarcoma growth using metabolite-targeting drugs.
Donor-Derived CD7 Chimeric Antigen Receptor T Cells for T-Cell Acute Lymphoblastic Leukemia: First-in-Human, Phase I Trial
Authors: Jing Pan, Yue Tan, Guoling Wang, Biping Deng, Zhuojun Ling, Weiliang Song, Samuel Seery, Yanlei Zhang, Shuixiu Peng, Jinlong Xu, Jiajia Duan, Zelin Wang, Xinjian Yu, Qinlong Zheng, Xiuwen Xu, Ying Yuan, Fangrong Yan, Zhenglong Tian, Kaiting Tang, Jiecheng Zhang, Alex H. Chang, Xiaoming Feng
Journal: Journal of Clinical Oncology (2021)

Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) have few options and poor prognosis. The aim was to assess donor-derived anti-CD7 chimeric antigen receptor (CAR) T-cell safety and efficacy in patients with r/r T-ALL.In this single-center, phase I trial, we administered anti-CD7 CAR T cells, manufactured from either previous stem-cell transplantation donors or new donors, to patients with r/r T-ALL, in single infusions at doses of 5 × 105 or 1 × 106 (±30%) cells per kilogram of body weight. The primary end point was safety with efficacy secondary.Twenty participants received infusions. Adverse events including cytokine release syndrome grade 1-2 occurred in 90% (n = 18) and grade 3-4 in 10% (n = 2), cytopenia grade 3-4 in 100% (n = 20), neurotoxicity grade 1-2 in 15% (n = 3), graft-versus-host disease grade 1-2 in 60% (n = 12), and viral activation grade 1-2 in 20% (n = 4). All adverse events were reversible, except in one patient who died through pulmonary hemorrhage related to fungal pneumonia, which occurred at 5.5 months, postinfusion. Ninety percent (n = 18) achieved complete remission with seven patients proceeding to stem-cell transplantation. At a median follow-up of 6.3 months (range, 4.0-9.2), 15 remained in remission. CAR T cells were still detectable in five of five patients assessed in month 6, postinfusion. Although patients' CD7-positive normal T cells were depleted, CD7-negative T cells expanded and likely alleviated treatment-related T-cell immunodeficiency.Among 20 patients with r/r T-ALL enrolled in this trial, donor-derived CD7 CAR T cells exhibited efficient expansion and achieved a high complete remission rate with manageable safety profile. A multicenter, phase II trial of donor-derived CD7 CAR T cells is in progress (NCT04689659).
Brain-wide Cas9-mediated cleavage of a gene causing familial Alzheimer’s disease alleviates amyloid-related pathologies in mice
Authors: Yangyang Duan, Tao Ye, Zhe Qu, Yuewen Chen, Abigail Miranda, Xiaopu Zhou, Ka-Chun Lok, Yu Chen, Amy K. Y. Fu, Viviana Gradinaru, Nancy Y. Ip
Journal: Nature Biomedical Engineering (2021)
Author Correction: Targeting public neoantigens for cancer immunotherapy
Authors: Alexander H. Pearlman, Michael S. Hwang, Maximilian F. Konig, Emily Han-Chung Hsiue, Jacqueline Douglass, Sarah R. DiNapoli, Brian J. Mog, Chetan Bettegowda, Drew M. Pardoll, Sandra B. Gabelli, Nicholas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Shibin Zhou
Journal: Nature Cancer (2021)
O17-2 Tafasitamab + lenalidomide versus lenalidomide monotherapy in transplant-ineligible patients with R/R DLBCL (RE-MIND)
Authors: Grzegorz Nowakowski, Thomas Rodgers, Dario Marino, Maurizio Frezzato, Anna Maria Barbui, Claudia Castellino, Erika Meli, Nathan H. Fowler, Bruce Feinberg, Sascha Tillmanns, Stephan Parche, Gunter Fingerle-Rowson, Mark Winderlich, Sumeet Ambarkhane, Gilles Salles, Pier Luigi Zinzani
Journal: Annals of Oncology (2021)
MO16-5 Analysis of employment counseling for advanced cancer patients undergoing cancer drug therapy
Authors: Sawako Kaku, Kayoko Miyata, Rieko Simizu, Natsuko Moroi, Naoko Matsunaga, Miho Koitabashi, Mariko Shimizu, Mari Arai, Masako Yabumoto, Maeda Ryoko, Asuka Kijima, Kumie Sakihara, Takeyuki Wada, Satoru Iwasa, Hidehito Horinouchi, Eriko Satomi
Journal: Annals of Oncology (2021)
Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans
Authors: Kathleen B. Yates, Pierre Tonnerre, Genevieve E. Martin, Ulrike Gerdemann, Rose Al Abosy, Dawn E. Comstock, Sarah A. Weiss, David Wolski, Damien C. Tully, Raymond T. Chung, Todd M. Allen, Arthur Y. Kim, Sarah Fidler, Julie Fox, John Frater, Georg M. Lauer, W. Nicholas Haining, Debattama R. Sen
Journal: Nature Immunology (2021)
18F-FDG PET/CT and 68Ga-FAPI-4 PET/CT Findings of Bilateral Knee Osteoarthritis in a Patient With Uveal Malignant Melanoma
Authors: Özge Erol Fenercioğlu, Ediz Beyhan, Nurhan Ergül, Esra Arslan, Tevfik Fikret Çermik
Journal: Clinical Nuclear Medicine (2021)

We present the findings of 68Ga-FAPI-4 PET/CT and 18F-FDG PET/CT of a metastatic malignant melanoma patient with osteoarthritis. A 65-year-old woman with a history of metastatic uveal malignant melanoma was referred to 18F-FDG PET/CT for restaging after enucleation and chemotherapy. 18F-FDG PET/CT imaging showed high radiotracer uptake in liver metastases; additionally mild uptake due to osteoarthritis was observed in both knees. However, although 68Ga-FAPI-4 showed lower uptake in liver lesions, it showed a more prominent uptake in both knee joints compared with 18F-FDG.
Primary Percutaneous Coronary Intervention in a Case of Dual Right Coronary Artery Presenting As Acute Coronary Syndrome
Authors: Anish Hirachan
Journal: Clinical Cardiology and Cardiovascular Interventions (2021)

Dual right coronary artery (RCA) is a rare coronary anomaly. This anomaly is often undetected and may be totally asymptomatic to presenting as acute coronary syndrome. Here, we present a 41 year old male diabetic and smoker presented with acute onset severe chest pain of 30 minutes duration which was managed as acute coronary syndrome .His urgent coronary angiogram revealed single ostial origin of right coronary artery ( RCA) with total occlusion from proximal segment followed by double right coronary arteries with their respective distal branches.
Targeting immune dysfunction in aging
Authors: Simone Borgoni, Ksenia S. Kudryashova, Ksenia Burka, João Pedro de Magalhães
Journal: Ageing Research Reviews (2021)

Human aging is a multifactorial phenomenon that affects numerous organ systems and cellular processes, with the immune system being one of the most dysregulated. Immunosenescence, the gradual deterioration of the immune system, and inflammaging, a chronic inflammatory state that persists in the elderly, are among the plethora of immune changes that occur during aging. Almost all populations of immune cells change with age in terms of numbers and/or activity. These alterations are in general highly detrimental, resulting in an increased susceptibility to infections, reduced healing abilities, and altered homeostasis that promote the emergence of age-associated diseases such as cancer, diabetes, and other diseases associated with inflammation. Thanks to recent developments, several strategies have been proposed to target central immunological processes or specific immune subpopulations affected by aging. These therapeutic approaches could soon be applied in the clinic to slow down or even reverse specific age-induced immune changes in order to rejuvenate the immune system and prevent or reduce the impact of various diseases. Due to its systemic nature and interconnection with all the other systems in the body, the immune system is an attractive target for aging intervention because relatively targeted modifications to a small set of cells have the potential to improve the health of multiple organ systems. Therefore, anti-aging immune targeting therapies could represent a potent approach for improving healthspan. Here, we review aging changes in the major components of the immune system, we summarize the current immune-targeting therapeutic approaches in the context of aging and discuss the future directions in the field of immune rejuvenation.
Correction: Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic cell transplantation in older adolescents and young adults with Ph-negative acute lymphoblastic leukemia in first complete remission: analysis from CALGB 10403 and the CIBMTR
Authors: Matthew J. Wieduwilt, Wendy Stock, Anjali Advani, Selina Luger, Richard A. Larson, Martin Tallman, Frederick Appelbaum, Mei-Jie Zhang, Khalid Bo-Subait, Hai-Lin Wang, Vijaya Raj Bhatt, Bhagirathbhai Dholaria, Mary Eapen, Mehdi Hamadani, Omer Jamy, Tim Prestidge, Michael Pulsipher, David Ritchie, David Rizzieri, Akshay Sharma, Pere Barba, Brenda M. Sandmaier, Marcos de Lima, Partow Kebriaei, Mark Litzow, Wael Saber, Daniel Weisdorf
Journal: Leukemia (2021)
MO20-6 A prospective study comparing metabolic tools on PET scan with Mandard grading following NACT in SCC of esophagus
Authors: Naveen Kumar, S.V.S. Deo, Sandeep Bhoriwal, Raja Pramanik, Atul Sharma, Rakesh Kumar, Prasenjit Das, Sunil Kumar
Journal: Annals of Oncology (2021)
Associations of ultrafine and fine particles with childhood emergency room visits for respiratory diseases in a megacity
Authors: Jiakun Fang, Xiaoming Song, Hongbing Xu, Rongshan Wu, Jing Song, Yunfei Xie, Xin Xu, Yueping Zeng, Tong Wang, Yutong Zhu, Ningman Yuan, Jinzhu Jia, Baoping Xu, Wei Huang
Journal: Thorax (2021)

Background Ambient fine particulate matter with aerodynamic diameter less than 2.5 µm (PM 2.5 ) has been associated with deteriorated respiratory health, but evidence on particles in smaller sizes and childhood respiratory health has been limited. Methods We collected time-series data on daily respiratory emergency room visits (ERVs) among children under 14 years old in Beijing, China, during 2015–2017. Concurrently, size-fractioned number concentrations of particles in size ranges of 5–560 nm (PNC 5–560 ) and mass concentrations of PM 2.5 , black carbon (BC) and nitrogen dioxide (NO 2 ) were measured from a fixed-location monitoring station in the urban area of Beijing. Confounder-adjusted Poisson regression models were used to estimate excessive risks (ERs) of particle size fractions on childhood respiratory ERVs, and positive matrix factorisation models were applied to apportion the sources of PNC 5–560 . Results Among the 136 925 cases of all-respiratory ERVs, increased risks were associated with IQR increases in PNC 25–100 (ER=5.4%, 95% CI 2.4% to 8.6%), PNC 100–560 (4.9%, 95% CI 2.5% to 7.3%) and PM 2.5 (1.3%, 95% CI 0.1% to 2.5%) at current and 1 prior days (lag0–1). Major sources of PNC 5–560 were identified, including nucleation (36.5%), gasoline vehicle emissions (27.9%), diesel vehicle emissions (18.9%) and secondary aerosols (10.6%). Emissions from gasoline and diesel vehicles were found of significant associations with all-respiratory ERVs, with increased ERs of 6.0% (95% CI 2.5% to 9.7%) and 4.4% (95% CI 1.7% to 7.1%) at lag0–1 days, respectively. Exposures to other traffic-related pollutants (BC and NO 2 ) were also associated with increased respiratory ERVs. Conclusion Our findings suggest that exposures to higher levels of PNC 5–560 from traffic emissions could be attributed to increased childhood respiratory morbidity, which supports traffic emission control priority in urban areas.
CX-072 (pacmilimab), a Probody<b><sup>®</sup></b>PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study
Authors: Aung Naing, Fiona Thistlethwaite, Elisabeth G.E. De Vries, Ferry A.L.M. Eskens, Nataliya Uboha, Patrick A. Ott, Patricia LoRusso, Javier Garcia-Corbacho, Valentina Boni, Johanna Bendell, Karen A. Autio, Manreet Randhawa, Greg Durm, Marta Gil-Martin, Mark Stroh, Alison L. Hannah, Hendrik-Tobias Arkenau, Alexander Spira
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Probody ® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing ‘off-tumor’ toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1). Methods In the dose-escalation phase of this multicenter, open-label study ( NCT03013491 ), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1). Results An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, &gt;50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1). Conclusions Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression. Trial registration number NCT03013491 .
Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis
Authors: Victoria E. Wang, Bradley W. Blaser, Ravi K. Patel, Gregory K. Behbehani, Arjun A. Rao, Blythe Durbin-Johnson, Tommy Jiang, Aaron C. Logan, Matthew Settles, Gabriel N. Mannis, Rebecca Olin, Lloyd E. Damon, Thomas G. Martin, Peter H. Sayre, Karin M. Gaensler, Emma McMahon, Michael Flanders, Vivian Weinberg, Chun J. Ye, David P. Carbone, Pamela N. Munster, Gabriela K. Fragiadakis, Frank McCormick, Charalambos Andreadis
Journal: Blood Cancer Discovery (2021)

Abstract Acute myeloid leukemia (AML) patients refractory to induction therapy or relapsed within 1 year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in preclinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single-cell RNA sequencing using prospectively acquired patient specimens identified IFN response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well tolerated, with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies. Significance: This study demonstrates a favorable safety profile and promising clinical activity of ficlatuzumab and cytarabine in high-risk AML, thus supporting further investigation of this combination in a randomized trial. It also shows the utility of a novel application using multiplexed single-cell analyses to detect on-target activity and identify biomarkers of response. This article is highlighted in the In This Issue feature, p. 403
Iron Oxide Nanoparticles Promote Cx43-Overexpression of Mesenchymal Stem Cells for Efficient Suicide Gene Therapy during Glioma Treatment
Authors: Ai Li, Tianyuan Zhang, Ting Huang, Ruyi Lin, Jiafu Mu, Yuanqin Su, Hao Sun, Xinchi Jiang, Honghui Wu, Donghang Xu, Hongcui Cao, Xiaoyi Sun, Daishun Ling, Jianqing Gao
Journal: Theranostics (2021)

Background: Mesenchymal stem cells (MSCs) have been applied as a promising vehicle for tumour-targeted delivery of suicide genes in the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) suicide gene therapy against malignant gliomas.The efficiency of this strategy is largely dependent on the bystander effect, which relies on high suicide gene expression levels and efficient transportation of activated GCV towards glioma cells.However, up to now, the methods to enhance the bystander effect of this strategy in an efficient and safe way are still lacking and new approaches to improve this therapeutic strategy are required.Methods: In this study, MSCs were gene transfected using magnetosome-like ferrimagnetic iron oxide nanochains (MFIONs) to highly express HSV-tk.Both the suicide and bystander effects of HSV-tk expressed MSCs (MSCs-tk) were quantitatively evaluated.Connexin 43 (Cx43) expression by MSCs and glioma cells was measured under different treatments.Intercellular communication between MSCs and C6 glioma cells was examined using a dye transfer assay.Glioma tropism and the bio-distribution of MSCs-tk were observed.Anti-tumour activity was investigated in the orthotopic glioma of rats after intravenous administration of MSCs-tk followed by intraperitoneal injection of GCV.Results: Gene transfection using MFIONs achieved sufficient expression of HSV-tk and triggered Cx43 overexpression in MSCs.These Cx43 overexpressing MSCs promoted gap junction intercellular communication (GJIC) between MSCs and glioma cells, resulting in significantly inhibited growth of glioma through an improved bystander effect.Outstanding tumour targeting and significantly prolonged survival with decreased tumour size were observed after the treatment using MFION-transfected MSCs in glioma model rats. Conclusion:Our results show that iron oxide nanoparticles have the potential to improve the suicide gene expression levels of transfected MSCs, while promoting the GJIC formation between MSCs and tumour cells, which enhances the sensitivity of glioma cells to HSV-tk/GCV suicide gene therapy.
Targeted Deep Sequencing in Blast Phase Myeloproliferative Neoplasms
Authors: Ayalew Tefferi, Terra L. Lasho, Mythri Mudireddy, Christy Finke, Kebede H. Begna, Curtis A. Hanson, Rhett P. Ketterling, Naseema Gangat, Animesh Pardanani
Journal: Blood (2017)
Using State Hospitalization Databases to Improve Firearm Injury Data—A Step in the Right Direction
Authors: Ashley B. Hink
Journal: JAMA Network Open (2021)

Yu-Tien Hsu, MD, MPH; Ya-Wen Chen, MD, MPH; David C. Chang, PhD, MPH, MBA; Numa P. Perez, MD; Maggie L. Westfal, MD, MPH; Ya-Ching Hung, MD, MPH; Cassandra M. Kelleher, MD; Peter T. Masiakos, MD, MS; Chana A. Sacks, MD, MPH
<i>NECTIN4</i> Heterogeneity and Molecular Diversity in Bladder Cancers: Deconstructing the Activity of An Antibody–Drug Conjugate
Authors: Min Yuen Teo, Jonathan E. Rosenberg
Journal: Clinical Cancer Research (2021)

Nectin-4 is the target for enfortumab vedotin, a novel antibody-drug conjugate. NECTIN4 gene expression differs considerably across different molecular subtypes and is shown to be important for enfortumab vedotin efficacy.See related article by Chu et al., p. 5123.