tbuckley/cabot-search huggingface dataset:
Intratumoral Heterogeneity in a Patient With Metastatic Thymic Carcinoma on 18F-FDG, 68Ga-DOTATATE, and 68Ga-FAPI04 PET/CT
Authors: Emine Göknur Isik, Serkan Kuyumcu, Zeynep Gözde Ozkan, Duygu Has Simsek, Yasemin Sanli
Journal: Clinical Nuclear Medicine (2021)

Herein, we present a 72-year-old woman with metastatic thymic carcinoma, referred for salvage peptide receptor radionuclide therapy with 177Lu-DOTATATE after completing all treatment options according to current clinical practice and guidelines. However, the patient was not eligible for 177Lu-DOTATATE peptide receptor radionuclide therapy and underwent 68Ga-FAPI04 PET/CT to assess the potential for a FAP-targeted therapy.
Optimizing risk-based breast cancer screening policies with reinforcement learning
Authors: Adam Yala, Peter G. Mikhael, Constance Lehman, Gigin Lin, Fredrik Strand, Yung-Liang Wan, Kevin Hughes, Siddharth Satuluru, Thomas Kim, Imon Banerjee, Judy Gichoya, Hari Trivedi, Regina Barzilay
Journal: Nature Medicine (2022)
Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial
Authors: Eva Versteijne, Jacob L. van Dam, Mustafa Suker, Quisette P. Janssen, Karin Groothuis, Janine M. Akkermans-Vogelaar, Marc G. Besselink, Bert A. Bonsing, Jeroen Buijsen, Olivier R. Busch, Geert-Jan M. Creemers, Ronald M. van Dam, Ferry A. L. M. Eskens, Sebastiaan Festen, Jan Willem B. de Groot, Bas Groot Koerkamp, Ignace H. de Hingh, Marjolein Y. V. Homs, Jeanin E. van Hooft, Emile D. Kerver, Saskia A. C. Luelmo, Karen J. Neelis, Joost Nuyttens, Gabriel M. R. M. Paardekooper, Gijs A. Patijn, Maurice J. C. van der Sangen, Judith de Vos-Geelen, Johanna W. Wilmink, Aeilko H. Zwinderman, Cornelis J. Punt, Geertjan van Tienhoven, Casper H. J. van Eijck
Journal: Journal of Clinical Oncology (2022)

The benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable pancreatic cancer remains controversial. Initial results of the PREOPANC trial failed to demonstrate a statistically significant overall survival (OS) benefit. The long-term results are reported.In this multicenter, phase III trial, patients with resectable and borderline resectable pancreatic cancer were randomly assigned (1:1) to neoadjuvant chemoradiotherapy or upfront surgery in 16 Dutch centers. Neoadjuvant chemoradiotherapy consisted of three cycles of gemcitabine combined with 36 Gy radiotherapy in 15 fractions during the second cycle. After restaging, patients underwent surgery followed by four cycles of adjuvant gemcitabine. Patients in the upfront surgery group underwent surgery followed by six cycles of adjuvant gemcitabine. The primary outcome was OS by intention-to-treat. No safety data were collected beyond the initial report of the trial.Between April 24, 2013, and July 25, 2017, 246 eligible patients were randomly assigned to neoadjuvant chemoradiotherapy (n = 119) and upfront surgery (n = 127). At a median follow-up of 59 months, the OS was better in the neoadjuvant chemoradiotherapy group than in the upfront surgery group (hazard ratio, 0.73; 95% CI, 0.56 to 0.96; P = .025). Although the difference in median survival was only 1.4 months (15.7 months v 14.3 months), the 5-year OS rate was 20.5% (95% CI, 14.2 to 29.8) with neoadjuvant chemoradiotherapy and 6.5% (95% CI, 3.1 to 13.7) with upfront surgery. The effect of neoadjuvant chemoradiotherapy was consistent across the prespecified subgroups, including resectable and borderline resectable pancreatic cancer.Neoadjuvant gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine improves OS compared with upfront surgery and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer.
Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates
Authors: Andrea Toth, Shelby Steinmeyer, Paranthaman Kannan, Jerilyn Gray, Courtney M. Jackson, Shibabrata Mukherjee, Martin Demmert, Joshua R. Sheak, Daniel Benson, Joseph Kitzmiller, Joseph A. Wayman, Pietro Presicce, Christopher Cates, Rhea Rubin, Kashish Chetal, Yina Du, Yifei Miao, Mingxia Gu, Minzhe Guo, Vladimir V. Kalinichenko, Suhas G. Kallapur, Emily R. Miraldi, Yan Xu, Daniel Swarr, Ian Lewkowich, Nathan Salomonis, Lisa Miller, Jennifer S. Sucre, Jeffrey A. Whitsett, Claire A. Chougnet, Alan H. Jobe, Hitesh Deshmukh, William J. Zacharias
Journal: Science Translational Medicine (2022)

Perinatal inflammatory stress is associated with early life morbidity and lifelong consequences for pulmonary health. Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25 to 40% of preterm births. Severe chorioamnionitis with preterm birth is associated with significantly increased risk of pulmonary disease and secondary infections in childhood, suggesting that fetal inflammation may markedly alter the development of the lung. Here, we used intra-amniotic lipopolysaccharide (LPS) challenge to induce experimental chorioamnionitis in a prenatal rhesus macaque ( Macaca mulatta ) model that mirrors structural and temporal aspects of human lung development. Inflammatory injury directly disrupted the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure, particularly the close association and coordinated differentiation of alveolar type 1 pneumocytes and specialized alveolar capillary endothelium. Single-cell RNA sequencing analysis defined a multicellular alveolar signaling niche driving alveologenesis that was extensively disrupted by perinatal inflammation, leading to a loss of gas exchange surface and alveolar simplification, with notable resemblance to chronic lung disease in newborns. Blockade of the inflammatory cytokines interleukin-1β and tumor necrosis factor–α ameliorated LPS-induced inflammatory lung injury by blunting stromal responses to inflammation and modulating innate immune activation in myeloid cells, restoring structural integrity and key signaling networks in the developing alveolus. These data provide new insight into the pathophysiology of developmental lung injury and suggest that modulating inflammation is a promising therapeutic approach to prevent fetal consequences of chorioamnionitis.
Genomic Profiling of Lung Adenocarcinoma in Never-Smokers
Authors: Siddhartha Devarakonda, Yize Li, Fernanda Martins Rodrigues, Sumithra Sankararaman, Humam Kadara, Chandra Goparaju, Irena Lanc, Kymberlie Pepin, Saiama N. Waqar, Daniel Morgensztern, Jeffrey Ward, Ashiq Masood, Robert Fulton, Lucinda Fulton, Michael A. Gillette, Shankha Satpathy, Steven A. Carr, Ignacio Wistuba, Harvey Pass, Richard K. Wilson, Li Ding, Ramaswamy Govindan
Journal: Journal of Clinical Oncology (2021)

PURPOSE Approximately 10%-40% of patients with lung cancer report no history of tobacco smoking (never-smokers). We analyzed whole-exome and RNA-sequencing data of 160 tumor and normal lung adenocarcinoma (LUAD) samples from never-smokers to identify clinically actionable alterations and gain insight into the environmental and hereditary risk factors for LUAD among never-smokers. METHODS We performed whole-exome and RNA-sequencing of 88 and 69 never-smoker LUADs. We analyzed these data in conjunction with data from 76 never-smoker and 299 smoker LUAD samples sequenced by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium. RESULTS We observed a high prevalence of clinically actionable driver alterations in never-smoker LUADs compared with smoker LUADs (78%-92% v 49.5%; P &lt; .0001). Although a subset of never-smoker samples demonstrated germline alterations in DNA repair genes, the frequency of samples showing germline variants in cancer predisposing genes was comparable between smokers and never-smokers (6.4% v 6.9%; P = .82). A subset of never-smoker samples (5.9%) showed mutation signatures that were suggestive of passive exposure to cigarette smoke. Finally, analysis of RNA-sequencing data showed distinct immune transcriptional subtypes of never-smoker LUADs that varied in their expression of clinically relevant immune checkpoint molecules and immune cell composition. CONCLUSION In this comprehensive genomic and transcriptome analysis of never-smoker LUADs, we observed a potential role for germline variants in DNA repair genes and passive exposure to cigarette smoke in the pathogenesis of a subset of never-smoker LUADs. Our findings also show that clinically actionable driver alterations are highly prevalent in never-smoker LUADs, highlighting the need for obtaining biopsies with adequate cellularity for clinical genomic testing in these patients.
Hybrid PET/MRI in Staging Endometrial Cancer
Authors: Gabriele Ironi, Paola Mapelli, Alice Bergamini, Federico Fallanca, Giorgio Candotti, Chiara Gnasso, Gian Luca Taccagni, Miriam Sant'Angelo, Paola Scifo, Carolina Bezzi, Valentino Bettinardi, Paola Maria Vittoria Rancoita, Giorgia Mangili, Luca Bocciolone, Massimo Candiani, Luigi Gianolli, Francesco De Cobelli, Maria Picchio
Journal: Clinical Nuclear Medicine (2022)

The assessment of deep myometrial invasion (MI) and lymph node involvement is of utmost importance in the preoperative staging of endometrial cancer (EC). Imaging parameters derived respectively from MRI and PET have shown good predictive value. The main aim of the present study is to assess the diagnostic performance of hybrid 18F-FDG PET/MRI in EC staging, with particular focus on MI and lymphnodal involvement detection.Prospective monocentric study including 35 patients with biopsy-proven EC undergoing preoperative 18F-FDG PET/MRI (December 2018-March 2021) for staging purpose. Histological examination was the reference standard. PET (SUVmax, SUVmean with a threshold of 40% of SUVmax-SUVmean40, metabolic tumor volume, total lesion glycolysis) and MRI (volume index [VI], total tumor volume, tumor volume ratio [TVR], mean apparent diffusion coefficient, minimum apparent diffusion coefficient) parameters were calculated on the primary tumor, and their role in predicting EC risk group, the presence of lymphovascular space invasion (LVSI), and MI was assessed. Receiver operating characteristics analysis was used to assess the predictive value of PET and MRI parameters on EC characteristics.Patients' median age was 66.57 years (SD, 10.21 years). 18F-FDG PET/MRI identified the primary tumor in all patients. Twenty-two of 35 patients had high-risk EC and 13/35 low-risk disease; 13/35 presented LVSI, 22/35 had deep MI at histological examination, and 13/35 had p53 hyperexpression.PET/MRI was able to detect lymphnodal involvement with high accuracy and high specificity (sensitivity of 0.8571, specificity of 0.9286, accuracy of 0.9143), also showing a high negative predictive value (NPV) for lymphnodal involvement (NPV of 0.9630, positive predictive value [PPV] of 0.7500).The assessment of deep MI using PET/MRI correctly staged 27 patients (77.1%; sensitivity of 0.7273, specificity of 0.8462, accuracy of 0.7714), with also a good PPV (PPV of 0.8889, NPV of 0.647).MRI-derived total tumor volume, VI, and TVR were significant in predicting EC groups (high-risk vs low-risk patients) (P = 0.0059, 0.0235, 0.0181, respectively). MRI-derived volume, VI, TVR, and PET-derived metabolic tumor volume and total lesion glycolysis were able to predict LVSI (P = 0.0023, 0.0068, 0.0068, 0.0027, 0.01394, respectively). Imaging was not able to predict grading, presence of deep MI, nor hyperexpression of p53.18F-FDG PET/MRI has good accuracy in preoperative staging of EC; PET and MRI parameters have synergic role in preoperatively predicting LVSI, with MRI parameters being also predictive for EC risk group.
Characterization of Peptides Targeting Metastatic Tumor Cells as Probes for Cancer Detection and Vehicles for Therapy Delivery
Authors: Shraddha Subramanian, Alexes C. Daquinag, Solmaz AghaAmiri, Sukhen C. Ghosh, Ali Azhdarinia, Mikhail G. Kolonin
Journal: Cancer Research (2021)

Abstract Metastasis is the leading cause of cancer-related deaths, and metastatic cancers remain largely incurable due to chemoresistance. Biomarkers of metastatic cells are lacking, and probes that could be used to detect and target metastases would be highly valuable. Here we hypothesize that metastatic cancer cells express cell-surface receptors that can be harnessed for identification of molecules homing to metastases. Screening a combinatorial library in a mouse mammary tumor model of spontaneous metastasis identified cyclic peptides with tropism for cancer cells disseminated to the lungs. Two lead peptides, CLRHSSKIC and CRAGVGRGC, bound murine and human cells derived from breast carcinoma and melanoma in culture and were selective for metastatic cells in vivo. In mice, peptide CRAGVGRGC radiolabeled with 67Ga for biodistribution analysis demonstrated selective probe homing to lung metastases. Moreover, systemic administration of 68Ga-labeled CRAGVGRGC enabled noninvasive imaging of lung metastases in mice by PET. A CRAGVGRGC-derived peptide induced apoptosis upon cell internalization in vitro and suppressed metastatic burden in vivo. Colocalization of CLRHSSKIC and CRAGVGRGC with N-cadherin+/E-cadherin− cells indicated that both peptides are selective for cancer cells that have undergone the epithelial-to-mesenchymal transition. We conclude that CRAGVGRGC is useful as a probe to facilitate the development of imaging modalities and therapies targeting metastases. Significance: This study identifies new molecules that bind metastatic cells and demonstrates their application as noninvasive imaging probes and vehicles for cytotoxic therapy delivery in preclinical cancer models.
Hyperpolarized Carbon-13 MRI for Early Response Assessment of Neoadjuvant Chemotherapy in Breast Cancer Patients
Authors: Ramona Woitek, Mary A. McLean, Stephan Ursprung, Oscar M. Rueda, Raquel Manzano Garcia, Matthew J. Locke, Lucian Beer, Gabrielle Baxter, Leonardo Rundo, Elena Provenzano, Joshua Kaggie, Andrew Patterson, Amy Frary, Johanna Field-Rayner, Vasiliki Papalouka, Justine Kane, Arnold J.V. Benjamin, Andrew B. Gill, Andrew N. Priest, David Y. Lewis, Roslin Russell, Ashley Grimmer, Brian White, Beth Latimer-Bowman, Ilse Patterson, Amy Schiller, Bruno Carmo, Rhys Slough, Titus Lanz, James Wason, Rolf F. Schulte, Suet-Feung Chin, Martin J. Graves, Fiona J. Gilbert, Jean E. Abraham, Carlos Caldas, Kevin M. Brindle, Evis Sala, Ferdia A. Gallagher
Journal: Cancer Research (2021)

Abstract Hyperpolarized 13C-MRI is an emerging tool for probing tissue metabolism by measuring 13C-label exchange between intravenously injected hyperpolarized [1–13C]pyruvate and endogenous tissue lactate. Here, we demonstrate that hyperpolarized 13C-MRI can be used to detect early response to neoadjuvant therapy in breast cancer. Seven patients underwent multiparametric 1H-MRI and hyperpolarized 13C-MRI before and 7–11 days after commencing treatment. An increase in the lactate-to-pyruvate ratio of approximately 20% identified three patients who, following 5–6 cycles of treatment, showed pathological complete response. This ratio correlated with gene expression of the pyruvate transporter MCT1 and lactate dehydrogenase A (LDHA), the enzyme catalyzing label exchange between pyruvate and lactate. Analysis of approximately 2,000 breast tumors showed that overexpression of LDHA and the hypoxia marker CAIX was associated with reduced relapse-free and overall survival. Hyperpolarized 13C-MRI represents a promising method for monitoring very early treatment response in breast cancer and has demonstrated prognostic potential. Significance: Hyperpolarized carbon-13 MRI allows response assessment in patients with breast cancer after 7–11 days of neoadjuvant chemotherapy and outperformed state-of-the-art and research quantitative proton MRI techniques.
The relationship between rising temperatures and malaria incidence in Hainan, China, from 1984 to 2010: a longitudinal cohort study
Authors: Zengmiao Wang, Yonghong Liu, Yapin Li, Guangze Wang, José Lourenço, Moritz Kraemer, Qixin He, Bernard Cazelles, Yidan Li, Ruixue Wang, Dongqi Gao, Yuchun Li, Wenjing Song, Dingwei Sun, Lu Dong, Oliver G Pybus, Nils Chr Stenseth, Huaiyu Tian
Journal: The Lancet Planetary Health (2022)

BackgroundThe influence of rising global temperatures on malaria dynamics and distribution remains controversial, especially in central highland regions. We aimed to address this subject by studying the spatiotemporal heterogeneity of malaria and the effect of climate change on malaria transmission over 27 years in Hainan, an island province in China.MethodsFor this longitudinal cohort study, we used a decades-long dataset of malaria incidence reports from Hainan, China, to investigate the pattern of malaria transmission in Hainan relative to temperature and the incidence at increasing altitudes. Climatic data were obtained from the local meteorological stations in Hainan during 1984–2010 and the WorldClim dataset. A temperature-dependent R0 model and negative binomial generalised linear model were used to decipher the relationship between climate factors and malaria incidence in the tropical region.FindingsOver the past few decades, the annual peak incidence has appeared earlier in the central highland regions but later in low-altitude regions in Hainan, China. Results from the temperature-dependent model showed that these long-term changes of incidence peak timing are linked to rising temperatures (of about 1·5°C). Further, a 1°C increase corresponds to a change in cases of malaria from –5·6% (95% CI –4·5 to –6·6) to –9·2% (95% CI –7·6 to –10·9) from the northern plain regions to the central highland regions during the rainy season. In the dry season, the change in cases would be 4·6% (95% CI 3·7 to 5·5) to 11·9% (95% CI 9·8 to 14·2) from low-altitude areas to high-altitude areas.InterpretationOur study empirically supports the idea that increasing temperatures can generate opposing effects on malaria dynamics for lowland and highland regions. This should be further investigated and incorporated into future modelling, disease burden calculations, and malaria control, with attention for central highland regions under climate change.FundingScientific and Technological Innovation 2030: Major Project of New Generation Artificial Intelligence, National Natural Science Foundation of China, Beijing Natural Science Foundation, National Key Research and Development Program of China, Young Elite Scientist Sponsorship Program by CAST, Research on Key Technologies of Plague Prevention and Control in Inner Mongolia Autonomous Region, and Beijing Advanced Innovation Program for Land Surface Science.
The PD-L1/4-1BB Bispecific Antibody–Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation in a Tumor-Localized Manner
Authors: Janet K. Peper-Gabriel, Marina Pavlidou, Lucia Pattarini, Aizea Morales-Kastresana, Thomas J. Jaquin, Catherine Gallou, Eva-Maria Hansbauer, Marleen Richter, Helene Lelievre, Alix Scholer-Dahirel, Birgit Bossenmaier, Celine Sancerne, Matthieu Riviere, Maximilien Grandclaudon, Markus Zettl, Rachida S. Bel Aiba, Christine Rothe, Veronique Blanc, Shane A. Olwill
Journal: Clinical Cancer Research (2022)

While patients responding to checkpoint blockade often achieve remarkable clinical responses, there is still significant unmet need due to resistant or refractory tumors. A combination of checkpoint blockade with further T-cell stimulation mediated by 4-1BB agonism may increase response rates and durability of response. A bispecific molecule that blocks the PD-1/PD-L1 axis and localizes 4-1BB co-stimulation to a PD-L1-positive tumor microenvironment (TME) or tumor draining lymph nodes could maximize antitumor immunity and increase the therapeutic window beyond what has been reported for anti-4-1BB monoclonal antibodies (mAbs).We generated and characterized the PD-L1/4-1BB bispecific molecule PRS-344/S095012 for target binding and functional activity in multiple relevant <em>in vitro</em> assays. Transgenic mice expressing human 4-1BB were transplanted with human PD-L1-expressing murine MC38 cells to assess <em>in vivo </em>antitumoral activity.PRS-344/S095012 bound to its targets with high affinity and efficiently blocked the PD-1/PD-L1 pathway, and PRS-344/S095012-mediated 4-1BB co-stimulation was strictly PD-L1 dependent. We demonstrated a synergistic effect of both pathways on T-cell stimulation with the bispecific PRS-344/S095012 being more potent than the combination of mAbs. PRS-344/S095012 augmented CD4+ and CD8+ T cells effector functions and enhanced antigen-specific T-cell stimulation. Finally, PRS-344/S095012 demonstrated strong antitumoral efficacy in an anti-PD-L1 resistant mouse model in which soluble 4-1BB was detected as an early marker for 4-1BB agonist activity.The PD-L1/4-1BB bispecific PRS-344/S095012 efficiently combines checkpoint blockade with a tumor-localized 4-1BB mediated stimulation burst to antigen-specific T cells, more potent than the combination of mAbs, supporting the advancement of PRS-344/S095012 towards clinical development.
Lung Cancer Cell of Origin: Controversy and Clinical Translational Implications
Authors: Jihan K. Osborne, John D. Minna
Journal: Cancer Research (2022)

Identifying the cell(s) of origin for lung cancer including detecting their expansion during “field cancerization” and understanding how to therapeutically target them for beneficial chemoprevention is an urgent need. In this issue of Cancer Research, Yin and colleagues provide new and potentially controversial information to this question using Gprc5a knockout genetically engineered mouse models of lung adenocarcinoma. Prior research identified several different cell types including resident lung stem/progenitor such as alveolar type II cells as well as terminally differentiated cells as candidates for the cancer-initiating cell. Yin and colleagues provide new information that the cancer-initiating cell in this model is the bronchioalveolar stem cell. See related article by Yin et al., p. 1025
中国特应性皮炎患者使用杜匹鲁单抗的研究
Journal: British Journal of Dermatology (2022)

特应性皮炎是一种常见的皮肤疾病，其炎症过程极不平衡。受影响患者有湿疹样病变和强烈瘙痒。虽然轻度特应性皮炎可以用面霜和软膏成功治疗，但中度和重度疾病通常需要使用影响全身的皮质类固醇和免疫抑制剂治疗。然而，这些治疗通常会导致不良副作用，因而不能长期使用。
Embolic Stroke of Undetermined Source: Can We Identify Subgroups With High Risk for Atrial Fibrillation Who May Benefit From Oral Anticoagulation?
Authors: Graeme J. Hankey
Journal: Circulation (2021)

mbolic stroke of undetermined source (ESUS) is a nonlacunar ischemic stroke on brain imaging without a clear embolic source after a minimum standard evaluation.This evaluation includes arterial imaging, echocardiography, cardiac rhythm monitoring for 24 hours, and laboratory tests of hemoglobin A1c and lipids. 1 ESUS is a subgroup of cryptogenic ischemic stroke, and it constitutes one-fifth of all ischemic strokes. 1 Potential embolic sources include nonstenosing atherosclerotic plaque, atrial cardiopathies, and paroxysmal atrial fibrillation (AF). 1 The annual risk of recurrent stroke after ESUS is about 5% despite aspirin thromboprophylaxis, 1 and most recurrent strokes are cardioembolic or ESUS again, 2 raising the hypothesis that subclinical AF may underpin an important, preventable proportion of ESUS and associated recurrent strokes.