tbuckley/cabot-search huggingface dataset:
Trends in Accuracy and Comprehensiveness of Pathology Reports for Resected NSCLC in a High Mortality Area of the United States
Authors: Matthew P. Smeltzer, Yu-Sheng Lee, Nicholas R. Faris, M.Div, Carrie Fehnel, Olawale Akinbobola, Meghan Meadows-Taylor, David Spencer, Elizabeth Sales, Sherry Okun, Christopher Giampapa, Amal Anga, Alicia Pacheco, Meredith A. Ray, Raymond U. Osarogiagbon
Journal: Journal of Thoracic Oncology (2021)

IntroductionComplete and accurate pathology reports are vital to postoperative prognostication and management. We evaluated the impact of three interventions across a diverse group of hospitals on pathology reports of postresection NSCLC.MethodsWe evaluated pathology reports for patients who underwent curative-intent surgical resection for NSCLC, at 11 institutions within four contiguous Dartmouth Hospital Referral Regions in Arkansas, Mississippi, and Tennessee from 2004 to 2020, for completeness and accuracy, before and after the following three quality improvement interventions: education (feedback to heighten awareness); synoptic reporting; and a lymph node specimen collection kit. We compared the proportion of pathology reports with the six most important items for postoperative management (specimen type, tumor size, histologic type, pathologic [p] T-category, pN-category, margin status) across the following six patient cohorts: preintervention control, postintervention with four different combinations of interventions, and a contemporaneous nonintervention external control.ResultsIn the postintervention era, the odds of reporting all key items were eight times higher than those in the preintervention era (OR = 8.3, 95 % confidence interval [CI]: 6.7–10.2, p < 0.0001). There were sixfold and eightfold increases in the odds of accurate pT- and pN-category reporting in the postintervention era compared with the preintervention era (pT OR = 5.7, 95 % CI: 4.7–6.9; pN OR = 8.0, 95 % CI: 6.5–10.0, both p < 0.0001). Within the intervention groups, the odds of reporting all six key items, accurate pT category, and accurate pN-category were highest in patients who received all three interventions.ConclusionsGaps in the quality of NSCLC pathologic reportage can be identified, quantified, and corrected by rationally designed interventions.
Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric <scp>Castleman</scp> disease
Authors: Yoshito Nishimura, David C. Fajgenbaum, Sheila K. Pierson, Noriko Iwaki, Asami Nishikori, Mitsuhiro Kawano, Naoya Nakamura, Koji Izutsu, Kengo Takeuchi, Midori Filiz Nishimura, Yoshinobu Maeda, Fumio Otsuka, Kazuyuki Yoshizaki, Eric Oksenhendler, Frits van Rhee, Yasuharu Sato
Journal: American Journal of Hematology (2021)

Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome is a heterogeneous entity manifesting with a constellation of symptoms described above that can occur in the context of idiopathic multicentric Castleman disease (iMCD) as well as infectious diseases, malignancies, and rheumatologic disorders. So, iMCD-TAFRO is an aggressive subtype of iMCD with TAFRO syndrome and often hyper-vascularized lymph nodes. Since we proposed diagnostic criteria of iMCD-TAFRO in 2016, we have accumulated new insights on the disorder and additional cases have been reported worldwide. In this systematic review and cohort analysis, we established and validated a definition for iMCD-TAFRO. First, we searched PubMed and Japan Medical Abstracts Society databases using the keyword "TAFRO" to extract cases. Patients with possible systemic autoimmune diseases and hematologic malignancies were excluded. Our search identified 54 cases from 50 articles. We classified cases into three categories: (1) iMCD-TAFRO (TAFRO syndrome with lymph node histopathology consistent with iMCD), (2) possible iMCD-TAFRO (TAFRO syndrome with no lymph node biopsy performed and no other co-morbidities), and (3) TAFRO without iMCD or other co-morbidities (TAFRO syndrome with lymph node histopathology not consistent with iMCD or other comorbidities). Based on the findings, we propose an international definition requiring four clinical criteria (thrombocytopenia, anasarca, fever/hyperinflammatory status, organomegaly), renal dysfunction or characteristic bone marrow findings, and lymph node features consistent with iMCD. The definition was validated with an external cohort (the ACCELERATE Natural History Registry). The present international definition will facilitate a more precise and comprehensive approach to the diagnosis of iMCD-TAFRO.
Addition of 5% CO<sub>2</sub> to Inspiratory Gas Prevents Lung Injury in an Experimental Model of Pulmonary Artery Ligation
Authors: Ines Marongiu, Elena Spinelli, Eleonora Scotti, Alessandra Mazzucco, Yu-Mei Wang, Leonardo Manesso, Giulia Colussi, Osvaldo Biancolilli, Michele Battistin, Thomas Langer, Francesca Roma, Gianluca Lopez, Caterina Lonati, Valentina Vaira, Lorenzo Rosso, Stefano Ferrero, Stefano Gatti, Alberto Zanella, Antonio Pesenti, Tommaso Mauri
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Unilateral ligation of the pulmonary artery may induce lung injury through multiple mechanisms, which might be dampened by inhaled CO
Abstract 841: Risk of hepatobiliary &amp; pancreatic cancer in inflammatory bowel disease
Authors: Jingru Yu, Erle Refsum, Lise M. Helsingen, Trine Folseraas, Alexander Ploner, Paulina Wieszczy, Ishita Barua, Henriette C. Jodal, Espen Melum, Magnus Løberg, Johannes Blom, Michael Bretthauer, Hans-Olov Adami, Mette Kalager, Weimin Ye
Journal: Cancer Research (2021)

Abstract Background: The risk of hepatobiliary and pancreatic cancer in patients with inflammatory bowel disease (IBD) with or without concomitant primary sclerosing cholangitis (PSC) has not been reliably quantified in large, prospective studies with long-term follow-up. Methods: We performed a population cohort study of all patients diagnosed with IBD in Norway and Sweden from 1987 to 2015. Participants were followed through linkage to national cancer, cause of death and population registers. We calculated standardized incidence ratios (SIR) with 95% confidence intervals (CIs) and absolute risk of hepatobiliary and pancreatic cancer by PSC status and other clinical characteristics. Results: We identified 141,960 IBD patients, 4,548 (3.2%) of these with concomitant PSC. During a median follow-up time of 10.0 years, we identified 479 biliary tract cancers (SIR 5.2, 95% CI 4.7-5.7), 127 hepatocellular carcinomas (SIR 2.1, 95% CI 1.8-2.5) and 282 pancreatic cancers (SIR 1.3, 95% CI 1.2-1.5). The relative risks were considerably higher in patients with PSC, with SIRs of 142 (95% CI 125-160) for biliary tract, 27.7 (95% CI 19.4-38.5) for hepatocellular, and 9.0 (95% CI 6.3-12.6) for pancreatic cancer. For IBD patients without PSC, we found SIRs of 2.5 (95% CI 2.2-2.9), 1.5 (1.2-1.8), and 1.2 (1.1-1.4) for biliary tract cancer, hepatocellular carcinoma, and pancreatic cancer, respectively. Conclusion: Patients with IBD experience a substantially increased risk of biliary tract cancer. Although the risk is largely confined to patients with concomitant PSC, non-PSC patients also confer a moderate excess risk. Citation Format: Jingru Yu, Erle Refsum, Lise M. Helsingen, Trine Folseraas, Alexander Ploner, Paulina Wieszczy, Ishita Barua, Henriette C. Jodal, Espen Melum, Magnus Løberg, Johannes Blom, Michael Bretthauer, Hans-Olov Adami, Mette Kalager, Weimin Ye. Risk of hepatobiliary &amp; pancreatic cancer in inflammatory bowel disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 841.
Holmium Laser Enucleation of the Prostate (HoLEP) in patients on active surveillance for low risk prostate cancer: an analysis on oncological and functional outcomes
Authors: L.J. Tay, M. Kulkarni, A. Zargaran, E. Spiers, R. Popert, B. Challacombe, M. Hadjipavlou
Journal: European Urology (2021)
Abstract 647: CXCL17 as a prognostic biomarker for aggressive cutaneous squamous cell carcinoma
Authors: Janmaris Marin Fermin, Maksudul MD Alam, Xin Gu, Ameya Asarkar, Cherie-Ann Nathan, Alok R. Khandelwal
Journal: Cancer Research (2021)

Abstract Cutaneous squamous cell cancer (cSCC) is one of the most rapidly increasing cancers in the USA, striking 200,000 Americans annually. cSCC is most often observed in the sun-exposed areas such as the head and neck region. Although most patients have an improved prognosis after surgical treatment, a subset carries an increased risk of local recurrence, nodal metastasis, and disease-specific death. CXCL17 (C-X-C Motif Chemokine Ligand 17) is the latest chemokine family member, and our preliminary studies identified a causative role of CXCL17 in skin tumorigenesis. Accordingly, we aimed to investigate the correlation between CXCL17 and clinicopathological factors associated with recurrence, metastasis, and disease-specific death in cSCC. A retrospective chart review was conducted to identify patients with cSCC at Louisiana State University Health Sciences Center Shreveport (LSUHSC-S) and Overton Brooks Veterans Affairs Medical Center. Tissue samples were immunostained for human CXCL17/VCC-1. Risk factors such as the depth of invasion, perineural invasion, tumor diameter, location, and differentiation were obtained from chart review/clinical databases and correlated with the expression of CXCL17. Among 42 subjects included in the analysis, the Histo-score of CXCL17 expression in cytoplasm and nucleus was higher in the malignant group compared to the normal skin group (p=0.01 and p=0.03, respectively). Interestingly, the Histo-score of CXCL17 expression was associated with perineural invasion (p=0.01) suggesting a role for CXCL17 in disease aggressiveness. Our results indicate a positive correlation between CXCL17 and cSCC aggressiveness. Increased expression of CXCL17 was associated with perineural invasion, a principal risk factor for recurrence, metastasis, and disease-specific death in cSCC patients. These results suggest that CXCL17 plays a role as a prognostic marker and warrants further exploration as a potential target for treatment in aggressive cSCC. Citation Format: Janmaris Marin Fermin, Maksudul MD Alam, Xin Gu, Ameya Asarkar, Cherie-Ann Nathan, Alok R. Khandelwal. CXCL17 as a prognostic biomarker for aggressive cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 647.
Hepatocellular Carcinoma — Origins and Outcomes
Authors: Robin K. Kelley, Tim F. Greten
Journal: New England Journal of Medicine (2021)

Pharmacologic inhibition of both the immune-checkpoint molecule PD-L1 and vascular endothelial growth factor improves survival among persons with hepatocellular carcinoma. The success of this combination therapy may depend on the context in which hepatocellular carcinoma arises.
Abstract 3067: Exploring strategies to modulate mitochondrial metabolism to alleviate tumor hypoxia
Authors: Martin Benej, Jinghai Wu, McKenzie Kreamer, Sandip Vibhute, Ioanna Papandreou, Nicholas C. Denko
Journal: Cancer Research (2021)

Abstract Radiation therapy is a standard type of treatment modality used as a part of curative or palliative treatment in more than 50% of all cancer patients. However, tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. Here, we explore and compare strategies to alleviate hypoxia by modifying the oxygen supply or demand within mouse tumor models. We used pODD-Luc, a dynamic in vivo luciferase reporter system that monitors relative levels of tumor hypoxia in real time. We show that in mouse tumor models, contrary to the reported results of human clinical trials, acute manipulation of systemic oxygen delivery significantly reduces the level of hypoxia. We then examined pharmacological manipulation of oxygen demand, which is an emerging trend in therapeutic efforts to sensitize tumors to anti-cancer therapy. Mitochondrial oxygen consumption (OCR) constitutes more than 90% of cellular oxygen demand by coupling carbon source oxidation with ATP generation in a series of redox reactions transferring electrons from reduced cofactors to molecular oxygen. Mechanistically, a decrease in mitochondrial OCR would lead to increased oxygen availability within the tumor, allowing initially hypoxic areas to become re-oxygenated. We found that strategies that directly stimulate mitochondrial OCR exacerbate levels of hypoxia while OCR suppression in turn promotes tumor re-oxygenation. We have previously shown that papaverine, an FDA-approved phosphodiesterase 10A (PDE10A) inhibitor effectively reduces hypoxic tumor fractions in vivo by an off-target effect that inhibits mitochondrial complex I. Here we show that its novel derivative SMV-32 that acts as complex I inhibitor with reduced PDE10A effect mediates superior OCR inhibition in both orthotopic and heterotopic mouse tumor models. These findings further establish the direct impact of OCR manipulation on tumor hypoxia and support the role of mitochondrial metabolism as an attractive target to alleviate tumor hypoxia and overcome treatment resistance. Citation Format: Martin Benej, Jinghai Wu, McKenzie Kreamer, Sandip Vibhute, Ioanna Papandreou, Nicholas C. Denko. Exploring strategies to modulate mitochondrial metabolism to alleviate tumor hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3067.
Abstract 2465: The opposing regulation of ALDOA and FBP1 in Glucose metabolism contribute to cancer progression
Authors: Chien Hsiu Li, Yu-Chan Chang, Michael Hsiao
Journal: Cancer Research (2021)

Abstract Metabolism reprogramming and increased glycolysis of cancer are associated with rapid cell growth, motility, and resistance to drug treatment. Fructose-1, 6-bisphosphate (F-1,6-BP), an important product involvement in glucose metabolism, especially in cancer development. It is known that the essential enzymes of gluconeogenesis and glycolysis, fructose-1,6-bisphosphonates 1 (FBP1) and glycolytic enzyme aldolase A (ALDOA) expression are involved in the F-1,6-BP conversion process. Especially, increased expression of ALDOA has been identified to contribute to multiple human cancer development. However, the underlying molecular mechanism involvement of ALDOA and FBP1 on the switching of F-1,6-BP is still being uncovered. This study shows that the expression levels of ALDOA and FBP1 with an inversed correlation during the cancer progression, especially in lung adenocarcinoma and hepatocellular carcinoma. Immunoprecipitation and proteomics analyses revealed the candidates, including the anterior gradient 2 (AGR2), ubiquitin ligase gene cullin 4B (CUL4B), and telomeric repeat binding factor 1 (TERF1) are significantly correlated with ALDOA and FBP1 expression. We designed a specific peptide to interfere the interaction of candidates on both ALDOA and FBP1. Moreover, we evaluate the relative glucose metabolism events. Further, we raised the hypothesis that these candidates may serve as a modulator to regulate the conversion of F-1,6-BP and contribute to cancer progression, which can be used as a therapeutic target for further research. Citation Format: Chien Hsiu Li, Yu-Chan Chang, Michael Hsiao. The opposing regulation of ALDOA and FBP1 in Glucose metabolism contribute to cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2465.
Distinct mechanisms govern populations of myeloid-derived suppressor cells in chronic viral infection and cancer
Authors: Evgenii N. Tcyganov, Shino Hanabuchi, Ayumi Hashimoto, David Campbell, Gozde Kar, Timothy W.F. Slidel, Corinne Cayatte, Aimee Landry, Fernanda Pilataxi, Susana Hayes, Brian Dougherty, Kristin C. Hicks, Kathy Mulgrew, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Wei Guo, Sergei Grivennikov, Mohammed-Alkhatim A. Ali, Jean-Christophe Beltra, E. John Wherry, Yulia Nefedova, Dmitry I. Gabrilovich
Journal: Journal of Clinical Investigation (2021)

Myeloid-derived suppressor cells (MDSCs) are major negative regulators of immune responses in cancer and chronic infections. It remains unclear if regulation of MDSC activity in different conditions is controlled by similar mechanisms. We compared MDSCs in mice with cancer and lymphocytic choriomeningitis virus (LCMV) infection. Chronic LCMV infection caused the development of monocytic MDSCs (M-MDSCs) but did not induce polymorphonuclear MDSCs (PMN-MDSCs). In contrast, both MDSC populations were present in cancer models. An acquisition of immune-suppressive activity by PMN-MDSCs in cancer was controlled by IRE1α and ATF6 pathways of the endoplasmic reticulum (ER) stress response. Abrogation of PMN-MDSC activity by blockade of the ER stress response resulted in an increase in tumor-specific immune response and reduced tumor progression. In contrast, the ER stress response was dispensable for suppressive activity of M-MDSCs in cancer and LCMV infection. Acquisition of immune-suppressive activity by M-MDSCs in spleens was mediated by IFN-γ signaling. However, it was dispensable for suppressive activity of M-MDSCs in tumor tissues. Suppressive activity of M-MDSCs in tumors was retained due to the effect of IL-6 present at high concentrations in the tumor site. These results demonstrate disease- and population-specific mechanisms of MDSC accumulation and the need for targeting different pathways to achieve inactivation of these cells.
Abstract 2300: Overcoming TKI-resistance in NSCLC using SphK2 inhibitors
Authors: Nabiha Haleema Khan, Neelu Puri
Journal: Cancer Research (2021)

Abstract In 2020, 228,820 lung cancer cases and 135,720 deaths have been anticipated. NSCLC is currently treated with Tyrosine Kinase Inhibitors (TKIs) such as Erolitinib (ER; second generation) and Osimertinib (OR; third generation). However, patients often develop resistance to these drugs overtime. This acquired resistance to TKIs is due to a secondary T790M mutation in the kinase domain which could be responsible for inducing Epithelial Mesenchymal Transition (EMT). EMT is a vital process in development of metastasis and occurs, by downregulation of E-cadherin, and upregulation of proteins like N-cadherin and vimentin. Therefore, it is imperative to find other molecularly targeted therapies to combat TKI resistance. Sphingosine kinase (SphK) is a type of lipid kinase that phosphorylates sphingosine to sphingosine-phosphates. There are two functional SphK isoforms (SphK1 and SphK2) that have been identified and characterized in mammalian cells. As a member of the SphK family, SphK2 activity can be stimulated by a series of cytokines such as EGF and VEGF, and acts as an oncogenic enzyme in tumor cells. Overexpression of SphK2 has been demonstrated in many cancer types and is closely related with cancer progression and the poor survival of patients. Currently minimal studies have been done on lung cancer and SphK2. This study investigated the roles of SphK2 in OR-resistant wild-type EGFR H2170 and H358, EGFR-mutated and TKI-sensitive H3255 cells (L858R mutation), and EGFR mutated TKI-resistant H1975 cells (L858R and T790M mutation). The modulation of EMT biomarkers was determined by qPCR. Key EMT regulators such as vimentin and N-cadherin were upregulated by 2.5 and 1.5-fold, respectively, while E-cadherin was downregulated by 1.5-fold. Immunofluorescence studies with Vimentin showed that H1975OR cells were elongated and have a mesenchymal phenotype compared to the H3255OR and their respective parental counterparts. MTT studies done using inhibitors of SphK2 in NSCLC OR-resistant cells showed a 3.0-fold decrease in cell viability in comparison to a 2.0-fold decrease in their parental counterparts. In wound closure assays at 24 hours the wound closure was 1.5-fold less in cells treated with SphK2 inhibitor as compared to parental cells treated with SphK2 inhibitors. Currently studies are being done to determine expression of SphK2 in late and early stage NSCLC tumors. In conclusion SphK2 was found to be a crucial positive regulator of different modes of cell migration and a key biomarker in combating TKI-resistance in NSCLC. Citation Format: Nabiha Haleema Khan, Neelu Puri. Overcoming TKI-resistance in NSCLC using SphK2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2300.
The S100A9/Fto Axis Induces Formation of RNA:DNA Hybrids That Serve As Damps Initiating Myeloid Skewing & Genetic Injury in MDS
Authors: Erika Eksioglu, Xianghong Chen, Pingyan Cheng, Jinhong Liu, Kathy McGraw, David A Sallman, Eric Padron, Alan F List, Sheng Wei
Journal: Blood (2017)
Abstract LB066: Assessing the safety liability of t-cell bispecific (TCB) antibodies using Ogans-on-Chips technology
Authors: S. Jordan Kerns, Ville Kujala, Marianne Kanellias, John Sauld, William Tien-Street, Heather S. Grant, Katia A. Karalis, Geraldine A. Hamilton, Lorna Ewart, Adrian B. Roth, Annie Moisan, Nikolche Gjorevski
Journal: Cancer Research (2021)

Abstract T-cell bispecific antibodies (TCBs) are a promising class of immunotherapeutic agents that promote tumor cell killing by physical crosslinking of effector T-cells to target expressing cells. While TCBs are effective in targeting less-immunogenic tumors, they are subject to safety liabilities in normal tissues, which may express low levels of the target. Preclinical assessment of safety risks is crucial but species differences between human and rodent immune responses necessitate the development of advanced human cell-based models for TCB safety profiling. While conventional killing assays are experimentally tractable, they lack physiological organization and cytoarchitecture and often fail to accurately predict efficacy and off-tumor cytotoxicity. Here, we show the robustness of our Intestine-Chip to capture variability in immune cell activation at physiologically relevant TCB concentrations when immune cells are directly applied to the apical epithelium. With increased confidence in the predictive capabilities of the model, we then confirmed expected regional dependence to gastrointestinal (GI) toxicity of the TCB by showing elevated immune cell activation in the large- versus small-intestine. Further, we have demonstrated vascular recruitment and transmigration of circulating immune cells to the intestinal epithelium to more accurately capture the in vivo mechanisms of TCB-mediated toxicity. Together, these data show that our models are suitable for safety profiling of novel engineered immunotherapies and provide clinically relevant results. Citation Format: S. Jordan Kerns, Ville Kujala, Marianne Kanellias, John Sauld, William Tien-Street, Heather S. Grant, Katia A. Karalis, Geraldine A. Hamilton, Lorna Ewart, Adrian B. Roth, Annie Moisan, Nikolche Gjorevski. Assessing the safety liability of t-cell bispecific (TCB) antibodies using Ogans-on-Chips technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB066.