tbuckley/cabot-search huggingface dataset:
Abstract ES10-2: Immune therapy in the (neo) adjuvant setting
Authors: H McArthur
Journal: Cancer Research (2022)

Abstract Historically, the treatment of early-stage triple negative breast cancer (TNBC) has hinged on the administration of conventional cytotoxics. However, the curative-intent treatment landscape has recently evolved with the successful development of checkpoint blockade inhibitor (CPI) strategies. Specifically, on July 27, 2021, the United States FDA approved the PD-1 directed antibody, pembrolizumab, for high-risk early-stage TNBC together with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery based on the results of the randomized, phase 3 KEYNOTE-522 study. In this study, the addition of pembrolizumab to a platinum-, taxane- and anthracycline-based regimen conferred an absolute 13.6% improvement in pathologic complete response (pCR) in the intention-to-treat population at the first interim analysis, with benefits observed irrespective of PD-L1 status. Although the absolute benefit subsequently decreased to 7.5% at the third interim analysis, the event free survival (EFS) benefit was maintained. In fact, with a median follow-up of 39.1 months at the fourth interim analysis, the EFS was 15.7% versus 23.8% (HR 0.63, p= 0.00031) in favor of the CPI containing regimen. The Geparnuevo study, a modestly powered study in which randomized patients with early stage TNBC to receive neoadjuvant chemotherapy with or without durvalumab, a PD-L1 targeting CPI, did not meet its pCR primary endpoint; however, in a recent update reporting on secondary endpoints, improvements in invasive disease free survival (85.6% vs 77.2%), distant disease free survival (91.7% vs 78.4%) and overall survival (95.2% vs 83.5%) were reported in favor of the CPI-containing regimen. EFS data from the IMpassion031 study of neoadjuvant chemotherapy with or without the PD-L1 targeting CPI, atezolizumab, are anticipated after an absolute 16.5% improvement in pCR was reported in the intention-to-treat population with the addition of the CPI, with benefits observed regardless of PD-L1 status. Studies evaluating the role of CPI strategies in the adjuvant setting are also underway. For example, pembrolizumab is being evaluated as monotherapy for patients with residual TNBC after neoadjuvant chemotherapy in the SWOG 1418 study and atezolizumab is being administered with adjuvant chemotherapy after upfront surgery for early-stage TNBC in the IMpassion030/ALEXANDRA study. Studies evaluating curative-intent CPI and targeted therapies and/or local therapies are underway or planned. Available data, current controversies and future directions will be discussed. Citation Format: H McArthur. Immune therapy in the (neo) adjuvant setting [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES10-2.
RELATIONSHIP BETWEEN PARAMETERS OF RIGHT VENTRICULAR HEMODYNAMICS TO OUTCOMES IN COVID-19: CLINICAL AND ECHOCARDIOGRAPHIC COMPARISONS BETWEEN THE FIRST AND SECOND WAVES OF THE PANDEMIC
Authors: Nolberto Hernandez, Angel De la Cruz, Sai Doppalapudi, Kinnera Urlapu, Vikram Itare, Dongmin Shin, Jaydeep Mahasamudram, Nishant Allena, Diana Ronderos, Neelanjana Pandey, Alaa Omar, Jonathan N. Bella
Journal: Journal of the American College of Cardiology (2022)
INCIDENCE AND PREDICTORS OF SPONTANEOUS CORONARY ARTERY DISSECTION IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION- INSIGHTS FROM NATIONWIDE READMISSIONS DATABASE
Authors: Irfan Shafi, Rohit Maruthi, Aadil Lodhi, Hitesh Raheja, Vladimir Lakhter, Riyaz Bashir
Journal: Journal of the American College of Cardiology (2022)
Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis
Authors: Lin Lei, Alix Bruneau, Haquima El Mourabit, Justine Guégan, Trine Folseraas, Sara Lemoinne, Tom Hemming Karlsen, Bénédicte Hoareau, Romain Morichon, Ester Gonzalez‐Sanchez, Claire Goumard, Vlad Ratziu, Pierre Charbord, Jérémie Gautheron, Frank Tacke, Thierry Jaffredo, Axelle Cadoret, Chantal Housset
Journal: Hepatology (2022)

In liver fibrosis, myofibroblasts derive from HSCs and as yet undefined mesenchymal cells. We aimed to identify portal mesenchymal progenitors of myofibroblasts.Portal mesenchymal cells were isolated from mouse bilio-vascular tree and analyzed by single-cell RNA-sequencing. Thereby, we uncovered the landscape of portal mesenchymal cells in homeostatic mouse liver. Trajectory analysis enabled inferring a small cell population further defined by surface markers used to isolate it. This population consisted of portal fibroblasts with mesenchymal stem cell features (PMSCs), i.e., high clonogenicity and trilineage differentiation potential, that generated proliferative myofibroblasts, contrasting with nonproliferative HSC-derived myofibroblasts (-MF). Using bulk RNA-sequencing, we built oligogene signatures of the two cell populations that remained discriminant across myofibroblastic differentiation. SLIT2, a prototypical gene of PMSC/PMSC-MF signature, mediated profibrotic and angiogenic effects of these cells, which conditioned medium promoted HSC survival and endothelial cell tubulogenesis. Using PMSC/PMSC-MF 7-gene signature and slit guidance ligand 2 fluorescent in situ hybridization, we showed that PMSCs display a perivascular portal distribution in homeostatic liver and largely expand with fibrosis progression, contributing to the myofibroblast populations that form fibrotic septa, preferentially along neovessels, in murine and human liver disorders, irrespective of etiology. We also unraveled a 6-gene expression signature of HSCs/HSC-MFs that did not vary in these disorders, consistent with their low proliferation rate.PMSCs form a small reservoir of expansive myofibroblasts, which, in interaction with neovessels and HSC-MFs that mainly arise through differentiation from a preexisting pool, underlie the formation of fibrotic septa in all types of liver diseases.
Immunomodulation Strategies for the Successful Regeneration of a Tissue‐Engineered Vascular Graft
Authors: Fan Zhang, Martin W. King
Journal: Advanced Healthcare Materials (2022)

Cardiovascular disease leads to the highest morbidity worldwide. There is an urgent need to solve the lack of a viable arterial graft for patients requiring coronary artery bypass surgery. The current gold standard is to use the patient's own blood vessel, such as a saphenous vein graft. However, some patients do not have appropriate vessels to use because of systemic disease or secondary surgery. On the other hand, there is no commercially available synthetic vascular graft available on the market for small diameter (<6 mm) blood vessels like coronary, carotid, and peripheral popliteal arteries. Tissue-engineered vascular grafts (TEVGs) are studied in recent decades as a promising alternative to synthetic arterial prostheses. Yet only a few studies have proceeded to a clinical trial. Recent studies have uncovered that the host immune response can be directed toward increasing the success of a TEVG by shedding light on ways to modulate the macrophage response and improve the tissue regeneration outcome. In this review, the basic concepts of vascular tissue engineering and immunoengineering are considered. The state-of-art of TEVGs is summarized and the role of macrophages in TEVG regeneration is analyzed. Current immunomodulatory strategies based on biomaterials are also discussed.
Adult atopic eczema and the risk of dementia: A population-based cohort study
Authors: Alexa Magyari, Morgan Ye, David J. Margolis, Charles E. McCulloch, Steven R. Cummings, Kristine Yaffe, Sinéad M. Langan, Katrina Abuabara
Journal: Journal of the American Academy of Dermatology (2022)

Chronic inflammatory conditions have been linked to dementia, but little is known about the role of atopic eczema, an inflammatory condition recently recognized to be common among older adults.To determine whether active atopic eczema is associated with incident dementia.A longitudinal cohort study of 1,767,667 individuals aged 60 to 99 years registered with The Health Improvement Network, a primary care cohort in the United Kingdom. The diagnoses of atopic eczema and dementia were identified using medical record codes.The incidence of dementia was 57 per 10,000 person-years among those with atopic eczema during follow-up (12.1% of the population) compared with 44 per 10,000 person-years in the control group. This translated to a 27% increased risk of dementia (hazard ratio, 1.27; 95% CI, 1.23-1.30) in adjusted Cox proportional hazard models. Similar associations were observed in subgroup analyses of vascular dementia and Alzheimer's disease. The association persisted after additionally adjusting for the use of systemic corticosteroids (hazard ratio, 1.29; 95% CI, 1.26-1.33) and potential mediators (hazard ratio, 1.19; 95% CI, 1.16-1.22). More severe eczema was associated with a higher risk of dementia.Lack of detailed data on severity.Atopic eczema was associated with a small but increased risk of incident dementia. The association increased with the severity of atopic eczema.
Highlights from this issue
Authors: The Triumvirate
Journal: Thorax (2022)

The TriumvirateIn this edition of "Airwaves" we celebrate some of the unusual news items and colourful characters which have made the news in recent months.We also ponder the meaning (if any) of the current UK Government slogan "levelling up".In this month's journal you will find the unusual (bronchial cut-off sign) (see page 422) and the colourful (see the beautiful images derived from bronchoscopic needle based confocal laser endomicroscopy) (see page 370), with a dash of "levelling up".
Case 10-2022: A 78-Year-Old Man with Marked Ventricular Wall Thickening
Authors: Patricia A. Pellikka, David M. Dudzinski, Steven A. Lubitz, Teresa S.M. Tsang, Albree Tower-Rader, Amel Karaa
Journal: New England Journal of Medicine (2022)

A 78-year-old man was evaluated in the cardiology clinic because of biventricular myocardial wall thickening, mitral regurgitation, and ventricular arrhythmias. In his 20s, hypohidrosis and sports-related exertional dizziness had developed. Echocardiograms obtained over several decades showed thickened ventricles (shown in videos). Diagnostic tests were performed.
Transcriptomic Profiling of MSI-H/dMMR Gastrointestinal Tumors to Identify Determinants of Responsiveness to Anti–PD-1 Therapy
Authors: Keigo Chida, Akihito Kawazoe, Toshihiro Suzuki, Masahito Kawazu, Toshihide Ueno, Kazumasa Takenouchi, Yoshiaki Nakamura, Yasutoshi Kuboki, Daisuke Kotani, Takashi Kojima, Hideaki Bando, Saori Mishima, Takeshi Kuwata, Naoya Sakamoto, Jun Watanabe, Hiroyuki Mano, Masafumi Ikeda, Kohei Shitara, Itaru Endo, Tetsuya Nakatsura, Takayuki Yoshino
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Transcriptomic profiling was performed for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal tumors to determine the predictors of response to PD-1 blockade. Experimental Design: Thirty-six patients with MSI-H/dMMR gastrointestinal tumors, including gastric cancer, colorectal cancer, cholangiocarcinoma, small intestine cancer, and pancreatic cancer, being treated with PD-1 blockade were analyzed. We conducted the transcriptomic analysis of gastrointestinal tumors using RNA sequencing data, including the consensus molecular subtypes (CMS) of colorectal cancer. Results: Gene set enrichment analysis (GSEA) demonstrated that non-responders had upregulations of epithelial–mesenchymal transition, angiogenesis, hypoxia, mTORC1, TNF-α, KRAS, Wnt/β-catenin, TGF-β, and various metabolism-related signaling pathways. Meanwhile, the IFNγ pathway was enriched in responders. On the basis of the leading-edge analysis of GSEA, VEGF-A was significantly correlated with enriched pathways in non-responders. Patients with high VEGF-A expression, compared with those with low expression, had significantly shorter progression-free survival [PFS; median 4.8 months vs. not reached (NR), P = 0.032] and overall survival (median 11.1 months vs. NR, P = 0.045). Among 13 patients with colorectal cancer evaluable for CMS classification, the objective response rate was 100%, 0%, 0%, and 16.7% in CMS1, CMS2, CMS3, and CMS4, respectively. Patients with CMS1 had significantly longer PFS (NR vs. 4.8 months, P = 0.017) than those with CMS2, CMS3, or CMS4. Conclusions: Several transcriptomic features, including CMS classification and related genes, were associated with response to PD-1 blockade in MSI-H/dMMR gastrointestinal tumors. These findings can help develop predictive biomarkers or combination immunotherapies.
Essential medicines list in national cancer control plans: a secondary analysis from a global study
Authors: Evangelia Razis, Marie Kassapian, Charitini Andriakopoulou, Yehoda M Martei, Shalini Jayasekar Zurn, Nazik Hammad, Yannick Romero, Urania Dafni, André M Ilbawi, Dario Trapani
Journal: The Lancet Oncology (2022)
CLO22-067: Symptom Burden in Patients With Myelofibrosis who Have Moderate or Severe Thrombocytopenia: A Retrospective Analysis of Patients Enrolled in the PERSIST-2 Study
Authors: Ruben Mesa, Jeanne Palmer, Prithviraj Bose, Stephen Oh, Raajit Rampal, Sarah Buckley, Karisse Roman-Torres, Srdan Verstovsek, John Mascarenhas
Journal: Journal of the National Comprehensive Cancer Network (2022)

"CLO22-067: Symptom Burden in Patients With Myelofibrosis who Have Moderate or Severe Thrombocytopenia: A Retrospective Analysis of Patients Enrolled in the PERSIST-2 Study" published on 31 Mar 2022 by National Comprehensive Cancer Network.
Case 9-2022: A 56-Year-Old Woman with Fever, Myalgias, Diarrhea, and Cough
Authors: Jatin M. Vyas, Alison C. Castle, Patrick P. Bourgouin, Sarah E. Turbett
Journal: New England Journal of Medicine (2022)

A 56-year-old woman was admitted in the spring of 2020 because of fever, myalgias, diarrhea, and a dry cough. Six weeks earlier, she had had contact with a person with SARS-CoV-2 infection. She had mild ground-glass opacities on chest CT, as well as elevated aminotransferase levels and thrombocytopenia. A diagnostic test was performed.
mRNA cancer vaccines: Advances, trends and challenges
Authors: Qing He, Hua Gao, Dejiang Tan, Heng Zhang, Jun-zhi Wang
Journal: Acta Pharmaceutica Sinica B (2022)

Patients exhibit good tolerance to messenger ribonucleic acid (mRNA) vaccines, and the choice of encoded molecules is flexible and diverse. These vaccines can be engineered to express full-length antigens containing multiple epitopes without major histocompatibility complex (MHC) restriction, are relatively easy to control and can be rapidly mass produced. In 2021, the U.S. Food and Drug Administration (FDA) approved the first mRNA-based coronavirus disease 2019 (COVID-19) vaccine produced by Pfizer and BioNTech, which has generated enthusiasm for mRNA vaccine research and development. Based on the above characteristics and the development of mRNA vaccines, mRNA cancer vaccines have become a research hotspot and have undergone rapid development, especially in the last five years. This review analyzes the advances in mRNA cancer vaccines from various perspectives, including the selection and expression of antigens/targets, the application of vectors and adjuvants, different administration routes, and preclinical evaluation, to reflect the trends and challenges associated with these vaccines.
Author Correction: DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation
Authors: Haifa H. Jabara, Douglas R. McDonald, Erin Janssen, Michel J. Massaad, Narayanaswamy Ramesh, Arturo Borzutzky, Ingrid Rauter, Halli Benson, Lynda Schneider, Sachin Baxi, Mike Recher, Luigi D. Notarangelo, Rima Wakim, Ghassan Dbaibo, Majed Dasouki, Waleed Al-Herz, Isil Barlan, Safa Baris, Necil Kutukculer, Hans D. Ochs, Alessandro Plebani, Maria Kanariou, Gerard Lefranc, Ismail Reisli, Katherine A. Fitzgerald, Douglas Golenbock, John Manis, Sevgi Keles, Reuben Ceja, Talal A. Chatila, Raif S. Geha
Journal: Nature Immunology (2022)
Competition for refueling rather than cyclic reentry initiation evident in germinal centers
Authors: Ziqi Long, Bethan Phillips, Daniel Radtke, Michael Meyer-Hermann, Oliver Bannard
Journal: Science Immunology (2022)

Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation and proliferation in dark zones (DZs) and selection in light zones (LZs). GC B cells exit cell cycle a number of hours before entering LZs; therefore, continued participation in responses requires that they subsequently reenter cell cycle and move back to DZs, a process known as cyclic reentry. Affinity enhancements are thought to arise by B cells having to compete to initiate cyclic reentry each time they enter LZs, with T cell help being a major determinant; however, direct proof is lacking. Using Fucci2 mice, we confirmed an association between B cell receptor affinity and the first step of cyclic reentry, S phase initiation from a resting LZ state. However, neither T cell ablation nor MHCII deletion prevented resting LZ cells from reentering cell cycle, and this late G1-S transition was also not detectably restricted by competition. In contrast, using BATF induction as exemplar, we found that T cells "refueled" LZ cells in an affinity-dependent manner that was limited by both competition and cells' intrinsic antigen-acquiring abilities. Therefore, cyclic reentry initiation and B cell refueling are independently regulated in GCs, which may contribute to permitting cells of different competencies to be sustained alongside each other and allow T cell support to be provided across a dynamic range commensurate with affinity. We speculate that this less binary selection mechanism could help GCs nurture complex antibody maturation pathways and support the clonal diversity required for countering fast-evolving pathogens.
HYDROXYCHLOROQUINE ATTENUATES HERG CHANNEL BY PROMOTING THE MEMBRANE CHANNEL DEGRADATION: EVIDENCES FOR QT-INTERVAL PROLONGATION IN COVID-19 PATIENTS WITH HYDROXYCHLOROQUINE TREATMENT
Authors: Xiqiang Wang, Jing Liu, Ya Wang, Linyan Wei, Xiang Bu, Xiaoxiang Liu, Junkui Wang, Tingzhong Wang
Journal: Journal of the American College of Cardiology (2022)
IOLite: phase 1b trial of doublet/triplet combinations of dostarlimab with niraparib, carboplatin–paclitaxel, with or without bevacizumab in patients with advanced cancer
Authors: Timothy A Yap, Alberto Bessudo, Erika Hamilton, Jasgit Sachdev, Manish R Patel, Jordi Rodon, Lena Evilevitch, Meghan Duncan, Wei Guo, Sujatha Kumar, Sharon Lu, Bruce J Dezube, Nashat Gabrail
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Doublet combination therapies targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unknown if rational triplet combinations will be well tolerated and associated with improved antitumor activity. The objective of this trial was to determine the recommended phase 2 doses (RP2Ds) and to assess the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor dostarlimab in combination with (1) the poly(ADP-ribose) polymerase inhibitor niraparib with or without vascular endothelial growth factor inhibitor bevacizumab or (2) carboplatin–paclitaxel chemotherapy with or without bevacizumab, in patients with advanced cancer. Methods IOLite is a multicenter, open-label, multi-arm clinical trial. Patients with advanced solid tumors were enrolled. Patients received dostarlimab in combination with niraparib with or without bevacizumab or in combination with carboplatin–paclitaxel with or without bevacizumab until disease progression, unacceptable toxicity, or withdrawal from the study. Prespecified endpoints in all parts were to evaluate the dose-limiting toxicities (DLTs), RP2Ds, pharmacokinetics (PKs), and preliminary efficacy for each combination. Results A total of 55 patients were enrolled; patients received dostarlimab and: (1) niraparib in part A (n=22); (2) carboplatin–paclitaxel in part B (n=14); (3) niraparib plus bevacizumab in part C (n=13); (4) carboplatin–paclitaxel plus bevacizumab in part D (n=6). The RP2Ds of all combinations were determined. All combinations were safe and tolerable, with no new safety signals observed. DLTs were reported in 2, 1, 2, and 0 patients, in parts A–D, respectively. Preliminary antitumor activity was observed, with confirmed Response Evaluation Criteria in Solid Tumors v1.1 complete/partial responses reported in 4 of 22 patients (18.2%), 6 of 14 patients (42.9%), 4 of 13 patients (30.8%), and 3 of 6 (50.0%) patients, in parts A–D, respectively. Disease control rates were 40.9%, 57.1%, 84.6%, and 83.3%, in parts A–D, respectively. Dostarlimab PK was unaffected by any combinations tested. Coadministration of bevacizumab showed no impact on niraparib PKs. The overall mean PD-1 receptor occupancy was 99.0%. Conclusions Dostarlimab was well tolerated in both doublet and triplet regimens tested, with promising antitumor activity observed with all combinations. We observed higher disease control rates in the triplet regimens than in doublet regimens. Trial registration number NCT03307785 .
Abstract P2-12-16: Use of ovarian function suppression to preserve fertility during neoadjuvant chemotherapy oncologically safe in women under age 40: An inverse probability weighting adjusted analysis
Authors: Young Joo Lee, Seonok Kim, Hee J Kim
Journal: Cancer Research (2022)

Abstract Backgrounds Ovarian function suppression by gonadotropin releasing hormone agonist (GnRHa) is used to preserve fertility during neoadjuvant chemotherapy (NCT) in breast cancer especially in young women. Some results showed that patients with hormone-receptor (HR) negative breast cancer treated with NCT concurrent with GnRHa to preserve fertility had better outcome than without GnRHa. Methods From 2011 to 2014, 296 women aged under 40 years old with stage I to IIIA breast cancer, treated with NCT before surgery were analyzed. Primary endpoint was rate of pathologic complete response (pCR). Secondary endpoint was disease free survival (DFS) and overall survival (OS) between two groups categorized by concurrent with GnRHa during NCT to preserve fertility. Subgroup analysis was done with different HR status. Results Ninety-eight patients (33.1%) received concurrent GnRHa with NCT. Baseline characteristic showed no different between two groups except younger age with GnRHa group (p&amp;lt;0.001) and more use of GnRHa in HR+/HER2- subtype (p=0.023). pCR rate was higher with GnRHa group (8.08% vs 20.41%, p=0.002). However there was no significant difference in 5yr DFS between without GnRHa and with GnRHa (HR 1.4 95% CI 0.60 2-3.582) in entire cohort. In HR positive subcohort, 5yr DFS was not different between without GnRHa and with GnRH a group (80.9% and 87.7% respectively,p=0.643). In HR negative subcohort, 5yr DFS was 71.6% vs 70.6% (p=0.931). There were no overall survival difference between two group in entire and subcohort (p&amp;gt;0.05). Multivariable analysis also did not show survival improvement after use of GnRHa in HR- subtype (hazard ratio 2.166, (95% CI 0.746-6.292), p=0.155) and HR+ subtype (hazard ratio 1.231, (95% CI 0.205-7.411), p=0.820). Conclusion Among young women with breast cancer with negative hormone receptor treated with concomitant GnRHa achieved more pCR com compared with no GnRHa during chemotherapy. This result did not reach out to better survival outcome at this point. Trend to better outcome seen in survival curve implies further evaluation in this particular population. Citation Format: Young Joo Lee, Seonok Kim, Hee J Kim. Use of ovarian function suppression to preserve fertility during neoadjuvant chemotherapy oncologically safe in women under age 40: An inverse probability weighting adjusted analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-16.