tbuckley/cabot-search huggingface dataset:
Prognostic Value of Stromal Tumor-Infiltrating Lymphocytes in Young, Node-Negative, Triple-Negative Breast Cancer Patients Who Did Not Receive (neo)Adjuvant Systemic Therapy
Authors: Vincent M.T. de Jong, Yuwei Wang, Natalie D. ter Hoeve, Mark Opdam, Nikolas Stathonikos, Katarzyna Jóźwiak, Michael Hauptmann, Sten Cornelissen, Willem Vreuls, Efraim H. Rosenberg, Esther A. Koop, Zsuzsanna Varga, Carolien H.M. van Deurzen, Antien L. Mooyaart, Alicia Córdoba, Emma J. Groen, Joost Bart, Stefan M. Willems, Vasiliki Zolota, Jelle Wesseling, Anna Sapino, Ewa Chmielik, Ales Ryska, Annegien Broeks, Adri C. Voogd, Sherene Loi, Stefan Michiels, Gabe S. Sonke, Elsken van der Wall, Sabine Siesling, Paul J. van Diest, Marjanka K. Schmidt, Marleen Kok, Gwen M.H.E. Dackus, Roberto Salgado, Sabine C. Linn
Journal: Journal of Clinical Oncology (2022)

Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated with a favorable prognosis in TNBC. However, whether this association holds for patients who are node-negative (N0), young (< 40 years), and chemotherapy-naïve, and thus can be used for chemotherapy de-escalation strategies, is unknown.We selected all patients with N0 TNBC diagnosed between 1989 and 2000 from a Dutch population-based registry. Patients were age < 40 years at diagnosis and had not received (neo)adjuvant systemic therapy, as was standard practice at the time. Formalin-fixed paraffin-embedded blocks were retrieved (PALGA: Dutch Pathology Registry), and a pathology review including sTILs was performed. Patients were categorized according to sTILs (< 30%, 30%-75%, and ≥ 75%). Multivariable Cox regression was performed for overall survival, with or without sTILs as a covariate. Cumulative incidence of distant metastasis or death was analyzed in a competing risk model, with second primary tumors as competing risk.sTILs were scored for 441 patients. High sTILs (≥ 75%; 21%) translated into an excellent prognosis with a 15-year cumulative incidence of a distant metastasis or death of only 2.1% (95% CI, 0 to 5.0), whereas low sTILs (< 30%; 52%) had an unfavorable prognosis with a 15-year cumulative incidence of a distant metastasis or death of 38.4% (32.1 to 44.6). In addition, every 10% increment of sTILs decreased the risk of death by 19% (adjusted hazard ratio: 0.81; 95% CI, 0.76 to 0.87), which are an independent predictor adding prognostic information to standard clinicopathologic variables (χ2 = 46.7, P < .001).Chemotherapy-naïve, young patients with N0 TNBC with high sTILs (≥ 75%) have an excellent long-term prognosis. Therefore, sTILs should be considered for prospective clinical trials investigating (neo)adjuvant chemotherapy de-escalation strategies.
In CV disease, GLP-1 RAs and SGLT2 inhibitors reduce CV mortality
Authors: Michelle D. Kelsey, L. Kristin Newby
Journal: Annals of Internal Medicine (2022)

Source Citation Kanie T, Mizuno A, Takaoka Y, et al. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium–glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev. 2021;10:CD013650. 34693515
Soluble CD13 induces inflammatory arthritis by activating the bradykinin receptor B1
Authors: Pei-Suen Tsou, Chenyang Lu, Mikel Gurrea-Rubio, Sei Muraoka, Phillip L. Campbell, Qi Wu, Ellen N. Model, Matthew E. Lind, Sirapa Vichaikul, Megan N. Mattichak, William D. Brodie, Jonatan L. Hervoso, Sarah Ory, Camila I. Amarista, Rida Pervez, Lucas Junginger, Mustafa Ali, Gal Hodish, Morgan M. O’Mara, Jeffrey H. Ruth, Aaron M. Robida, Andrew J. Alt, Chengxin Zhang, Andrew G. Urquhart, Jeffrey N. Lawton, Kevin C. Chung, Tristan Maerz, Thomas L. Saunders, Vincent E. Groppi, David A. Fox, M. Asif Amin
Journal: Journal of Clinical Investigation (2022)

CD13, an ectoenzyme on myeloid and stromal cells, also circulates as a shed, soluble protein (sCD13) with powerful chemoattractant, angiogenic, and arthritogenic properties, which require engagement of a G protein-coupled receptor (GPCR). Here we identify the GPCR that mediates sCD13 arthritogenic actions as the bradykinin receptor B1 (B1R). Immunofluorescence and immunoblotting verified high expression of B1R in rheumatoid arthritis (RA) synovial tissue and fibroblast-like synoviocytes (FLSs), and demonstrated binding of sCD13 to B1R. Chemotaxis, and phosphorylation of Erk1/2, induced by sCD13, were inhibited by B1R antagonists. In ex vivo RA synovial tissue organ cultures, a B1R antagonist reduced secretion of inflammatory cytokines. Several mouse arthritis models, including serum transfer, antigen-induced, and local innate immune stimulation arthritis models, were attenuated in Cd13-/- and B1R-/- mice and were alleviated by B1R antagonism. These results establish a CD13/B1R axis in the pathogenesis of inflammatory arthritis and identify B1R as a compelling therapeutic target in RA and potentially other inflammatory diseases.
CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury
Authors: Yuki Sato, Akiko Oguchi, Yuji Fukushima, Kyoko Masuda, Naoya Toriu, Keisuke Taniguchi, Takahisa Yoshikawa, Xiaotong Cui, Makiko Kondo, Takeshi Hosoi, Shota Komidori, Yoko Shimizu, Harumi Fujita, Li Jiang, Yingyi Kong, Takashi Yamanashi, Jun Seita, Takuya Yamamoto, Shinya Toyokuni, Yoko Hamazaki, Masakazu Hattori, Yasunobu Yoshikai, Peter Boor, Jürgen Floege, Hiroshi Kawamoto, Yasuhiro Murakawa, Nagahiro Minato, Motoko Yanagita
Journal: Journal of Clinical Investigation (2021)

Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis, and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153/CD30 signaling in TLT formation and propose targeting the CD153/CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.
Treatment-free Survival after Immune Checkpoint Inhibitor Therapy versus Targeted Therapy for Advanced Renal Cell Carcinoma: 42-Month Results of the CheckMate 214 Trial
Authors: Meredith M. Regan, Opeyemi A. Jegede, Charlene M. Mantia, Thomas Powles, Lillian Werner, Robert J. Motzer, Nizar M. Tannir, Chung-Han Lee, Yoshihiko Tomita, Martin H. Voss, Elizabeth R. Plimack, Toni K. Choueiri, Brian I. Rini, Hans J. Hammers, Bernard Escudier, Laurence Albiges, Stephen Huo, Viviana Del Tejo, Brian Stwalley, Michael B. Atkins, David F. McDermott
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Patients discontinuing immuno-oncology regimens may experience periods of disease control without need for ongoing anticancer therapy, but toxicity may persist. We describe treatment-free survival (TFS), with and without toxicity. Patients and Methods: Data were analyzed from the randomized phase III CheckMate 214 trial of nivolumab plus ipilimumab (n = 550) versus sunitinib (n = 546) for treatment-naïve, advanced renal cell carcinoma (aRCC). TFS was estimated by the 42-month restricted mean times defined by the area between Kaplan–Meier curves for two time-to-event endpoints defined from randomization: time to protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was subdivided as TFS with and without toxicity by counting days with ≥1 grade ≥3 treatment-related adverse event (TRAE). Results: At 42 months since randomization, 52% of nivolumab plus ipilimumab and 39% of sunitinib intermediate/poor-risk patients were alive; 18% and 5% surviving treatment-free, respectively. Among favorable-risk patients, 70% and 73% of nivolumab plus ipilimumab and sunitinib patients were alive; 20% and 9% treatment-free. Over the 42-month period, mean TFS was over twice as long after nivolumab plus ipilimumab than sunitinib for intermediate/poor-risk (6.9 vs. 3.1 months) and three times as long for favorable-risk patients (11.0 vs. 3.7 months). Mean TFS with grade ≥3 TRAEs was a small proportion of time for both treatments (0.6 vs. 0.3 months after nivolumab plus ipilimumab vs. sunitinib for intermediate/poor-risk, and 0.9 vs. 0.3 months for favorable-risk patients). Conclusions: Patients initiating first-line nivolumab plus ipilimumab for aRCC spent more survival time treatment-free without toxicity versus those on sunitinib, regardless of risk group.
Toxic Effects from Ivermectin Use Associated with Prevention and Treatment of Covid-19
Authors: Courtney Temple, Ruby Hoang, Robert G Hendrickson
Journal: New England Journal of Medicine (2021)

Supplementary Appendix).Among adults who tested positive, those who were unvaccinated tended to be much younger, to have fewer coexisting conditions, and to have a lower socioeconomic status and were more likely to be men than those who were vaccinated; these differences tended to be especially pronounced in comparison with those who received the ChAdOx1 nCoV-19 vaccine (Table S2).Overall, 201 deaths from Covid-19 were caused by SARS-CoV-2 that had been tested and found to be S-positive or S-negative (Table 1).Among persons 18 to 39 years of age who had infections for which data on S gene status were available, no deaths occurred among those who were fully vaccinated, as compared with 17 deaths among those who were unvaccinated.Among those who were 40 to 59 years of age, vaccine effectiveness against death from Covid-19 was 88% (95% confidence interval [CI], 76 to 93) for ChAdOx1 nCoV-19 and 95% (95% CI, 79 to 99) for BNT162b2; vaccine effectiveness was 90% (95% CI, 84 to 94) and 87% (95% CI, 77 to 93), respectively, among those 60 years of age or older.Overall, vaccine effectiveness against death from the delta variant 14 or more days after the second vaccine dose was 90% (95% CI, 83 to 94) for BNT162b2 and 91% (95% CI, 86 to 94) for ChAdOx1 nCoV-19 (Table S3).A limitation of this study is the fact that it was based on an analysis of community samples.In addition, 1.8% of samples did not yield S gene categorization because of missing data in the Ct fields.In summary, we found that the BNT162b2 and ChAdOx1 nCoV-19 vaccines offered substantial protection against death from Covid-19 caused by the delta variant.
American College of Rheumatology Guidance for <scp>COVID</scp>‐19 Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: Version 4
Authors: Jeffrey R. Curtis, Sindhu R. Johnson, Donald D. Anthony, Reuben J. Arasaratnam, Lindsey R. Baden, Anne R. Bass, Cassandra Calabrese, Ellen M. Gravallese, Rafael Harpaz, Andrew Kroger, Rebecca E. Sadun, Amy S. Turner, Eleanor Anderson Williams, Ted R. Mikuls
Journal: Arthritis & Rheumatology (2022)

To provide guidance to rheumatology providers on the use of COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases (RMDs).
Extensive Biventricular Cardiac Sarcoidosis Detected on FDG PET/CT Using a 72-Hour Ketogenic Diet Preparation Protocol
Authors: Yang Lu
Journal: Clinical Nuclear Medicine (2022)

Abstract A 49-year-old man had right bundle-branch block, with decreased left ventricle ejection fraction of 43%. Cardiac MRI demonstrated abnormal multifocal delayed gadolinium enhancement involving both ventricles. Cardiac sarcoidosis was further confirmed at cardiac biopsy. Dedicated FDG PET/CT with 72-hour ketogenic diet preparation to suppress physiological myocardial uptake of FDG was performed for disease evaluation. PET/CT revealed multifocal abnormal uptake in both ventricles concordant with cardiac MRI findings, in addition to hypermetabolic lymphadenopathy. Six months later, posttreatment PET/CT with the same 72-hour ketogenic diet preparation showed good response with resolution of active inflammation.
Hepatic Angiosarcoma With Diffuse Increased 18F-FDG Uptake on PET/CT
Authors: Ziang Zhou, Xia Lu, Wei Wang, Jigang Yang
Journal: Clinical Nuclear Medicine (2022)

A 51-year-old woman was diagnosed with fulminant hepatic failure based on laboratory indexes. Contrast-enhanced CT demonstrated numerous, widespread lesions in all segments of the liver. 18 F-FDG PET/CT showed the abundant foci of increased 18 F-FDG uptake in the enlarged liver. The liver transplantation was performed due to fulminant hepatic failure. Postoperative pathology demonstrated diffused hepatic angiosarcoma, which should be included in the differential diagnosis of diffuse 18 F-FDG uptake hepatic lesions on PET/CT.
Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study
Authors: John Bridgewater, Peter Fletcher, Daniel H. Palmer, Hassan Z. Malik, Raj Prasad, Darius Mirza, Alan Anthony, Pippa Corrie, Stephen Falk, Meg Finch-Jones, Harpreet Wasan, Paul Ross, Lucy Wall, Jonathan Wadsley, Thomas R. Evans, Deborah Stocken, Clive Stubbs, Raaj Praseedom, Yuk Ting Ma, Brian Davidson, John Neoptolemos, Tim Iveson, David Cunningham, O. James Garden, Juan W. Valle, John Primrose
Journal: Journal of Clinical Oncology (2022)

PURPOSE The BILCAP study described a modest benefit for capecitabine as adjuvant therapy for curatively resected biliary tract cancer (BTC), and capecitabine has become the standard of care. We present the long-term data and novel exploratory subgroup analyses. METHODS This randomized, controlled, multicenter, phase III study recruited patients age 18 years or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer after resection with curative intent and an Eastern Cooperative Oncology Group performance status of &lt; 2. Patients were randomly assigned 1:1 to receive oral capecitabine (1,250 mg/m 2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation. The primary outcome was overall survival (OS). This study is registered with EudraCT 2005-003318-13. RESULTS Between March 15, 2006, and December 4, 2014, 447 patients were enrolled; 223 patients with BTC resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. At the data cutoff of January 21, 2021, the median follow-up for all patients was 106 months (95% CI, 98 to 108). In the intention-to-treat analysis, the median OS was 49.6 months (95% CI, 35.1 to 59.1) in the capecitabine group compared with 36.1 months (95% CI, 29.7 to 44.2) in the observation group (adjusted hazard ratio 0.84; 95% CI, 0.67 to 1.06). In a protocol-specified sensitivity analysis, adjusting for minimization factors, nodal status, grade, and sex, the OS hazard ratio was 0.74 (95% CI, 0.59 to 0.94). We further describe the prognostic impact of R status, grade, nodal status, and sex. CONCLUSION This long-term analysis supports the previous analysis, suggesting that capecitabine can improve OS in patients with resected BTC when used as adjuvant chemotherapy after surgery and should be considered as the standard of care.
Immune Determinants of the Association between Tumor Mutational Burden and Immunotherapy Response across Cancer Types
Authors: Neelam Sinha, Sanju Sinha, Cristina Valero, Alejandro A. Schäffer, Kenneth Aldape, Kevin Litchfield, Timothy A. Chan, Luc G.T. Morris, Eytan Ruppin
Journal: Cancer Research (2022)

Abstract The FDA has recently approved a high tumor mutational burden (TMB-high) biomarker, defined by ≥10 mutations/Mb, for the treatment of solid tumors with pembrolizumab, an immune checkpoint inhibitor (ICI) that targets PD1. However, recent studies have shown that this TMB-high biomarker is only able to stratify ICI responders in a subset of cancer types, and the mechanisms underlying this observation have remained unknown. The tumor immune microenvironment (TME) may modulate the stratification power of TMB (termed TMB power), determining if it will be predictive of ICI response in a given cancer type. To systematically study this hypothesis, we inferred the levels of 31 immune-related factors characteristic of the TME of different cancer types in The Cancer Genome Atlas. Integration of this information with TMB and response data of 2,277 patients treated with anti-PD1 identified key immune factors that determine TMB power across 14 different cancer types. We find that high levels of M1 macrophages and low resting dendritic cells in the TME characterized cancer types with high TMB power. A model based on these two immune factors strongly predicted TMB power in a given cancer type during cross-validation and testing (Spearman Rho = 0.76 and 1, respectively). Using this model, we predicted the TMB power in nine additional cancer types, including rare cancers, for which TMB and ICI response data are not yet publicly available. Our analysis indicates that TMB-high may be highly predictive of ICI response in cervical squamous cell carcinoma, suggesting that such a study should be prioritized. Significance: This study uncovers immune-related factors that may modulate the relationship between high tumor mutational burden and ICI response, which can help prioritize cancer types for clinical trials.
Mesenchymal-Type Neuroblastoma Cells Escape ALK Inhibitors
Authors: Ellen M. Westerhout, Mohamed Hamdi, Peter Stroeken, Natalia E. Nowakowska, Arjan Lakeman, Jennemiek van Arkel, Nancy E. Hasselt, Boris Bleijlevens, Nurdan Akogul, Franciska Haneveld, Alvin Chan, Peter van Sluis, Danny Zwijnenburg, Richard Volckmann, Carel J.M. van Noesel, Igor Adameyko, Tim van Groningen, Jan Koster, Linda J. Valentijn, Johan van Nes, Rogier Versteeg
Journal: Cancer Research (2021)

Abstract Cancer therapy frequently fails due to the emergence of resistance. Many tumors include phenotypically immature tumor cells, which have been implicated in therapy resistance. Neuroblastoma cells can adopt a lineage-committed adrenergic (ADRN) or an immature mesenchymal (MES) state. They differ in epigenetic landscape and transcription factors, and MES cells are more resistant to chemotherapy. Here we analyzed the response of MES cells to targeted drugs. Activating anaplastic lymphoma kinase (ALK) mutations are frequently found in neuroblastoma and ALK inhibitors (ALKi) are in clinical trials. ALKi treatment of ADRN neuroblastoma cells with a tumor-driving ALK mutation induced cell death. Conversely, MES cells did not express either mutant or wild-type ALK and were resistant to ALKi, and MES cells formed tumors that progressed under ALKi therapy. In assessing the role of MES cells in relapse development, TRAIL was identified to specifically induce apoptosis in MES cells and to suppress MES tumor growth. Addition of TRAIL to ALKi treatment of neuroblastoma xenografts delayed relapses in a subset of the animals, suggesting a role for MES cells in relapse formation. While ADRN cells resembled normal embryonal neuroblasts, MES cells resembled immature precursor cells, which also lacked ALK expression. Resistance to targeted drugs can therefore be an intrinsic property of immature cancer cells based on their resemblance to developmental precursors. Significance: In neuroblastoma, mesenchymal tumor cells lack expression of the tumor-driving ALK oncogene and are resistant to ALKi, but dual treatment with ALKi and mesenchymal cell–targeting TRAIL delays tumor relapse.
68Ga-FAPI-04 PET/CT in Solitary Choroid Plexus Metastasis From Renal Cell Carcinoma
Authors: Jian Yang, Aisheng Dong, Changjing Zuo
Journal: Clinical Nuclear Medicine (2022)

Intraventricular metastasis from extracranial tumor is rare. We describe MRI and 68Ga-FAPI-04 PET/CT findings in a case of histologically proved solitary choroid plexus metastasis from clear cell renal cell carcinoma. The tumor showed remarkable enhancement on MRI and increased FAPI uptake with high tumor-to-background activity ratio on PET/CT. This case indicates FAPI PET may be useful for detection of intraventricular metastasis from renal cell carcinoma.
An 18F-FDG-PET–Positive Mucoid Impaction With Ring Enhancement on CT Mimicking Lung Cancer
Authors: Nobuo Hatakeyama, Hiroyuki Hino, Eiji Takeuch, Shoji Sakiyama, Tsutomu Shinohara
Journal: Clinical Nuclear Medicine (2022)

Abstract We encountered a case of an 18 F-FDG PET–positive solitary nodule with ring enhancement on CT mimicking lung cancer in the left S6 region of an 80-year-old woman. Since transbronchial biopsy by endobronchial ultrasonography with a guide sheath could not obtain sufficient material, despite the guide sheath being placed within the lesion, the patient underwent thoracoscopic partial left S6 resection. The nodule was diagnosed as acquired cystic bronchiectasis and mucoid impaction associated with chronic inflammation. The ring-shaped enhancement and the 18 F-FDG uptake may reflect angiogenesis in the cystic wall and accumulation of viable inflammatory cells in the wall and inner space, respectively.
Dapagliflozin and new-onset type 2 diabetes in patients with chronic kidney disease or heart failure: pooled analysis of the DAPA-CKD and DAPA-HF trials
Authors: Peter Rossing, Silvio E Inzucchi, Priya Vart, Niels Jongs, Kieran F Docherty, Pardeep S Jhund, Lars Køber, Mikhail N Kosiborod, Felipe A Martinez, Piotr Ponikowski, Marc S Sabatine, Scott D Solomon, David L DeMets, Olof Bengtsson, Magnus Lindberg, Anna Maria Langkilde, Mikaela Sjöstrand, Bergur V Stefansson, Cecilia Karlsson, Glenn M Chertow, Fan Fan Hou, Ricardo Correa-Rotter, Robert D Toto, David C Wheeler, John J V McMurray, Hiddo J L Heerspink
Journal: The Lancet Diabetes & Endocrinology (2021)
In patients with stable CVD receiving statins, evolocumab reduced acute arterial events across all vascular territories
Authors: Baher Al Abbasi, Steven Borzak
Journal: Annals of Internal Medicine (2022)

Oyama K, Giugliano RP, Tang M, et al. Effect of evolocumab on acute arterial events across all vascular territories: results from the FOURIER trial. Eur Heart J. 2021;42:4821-9. 34537830.