tbuckley/cabot-search huggingface dataset:
No Strong Evidence for Ruling Out the Role of Coagulation in Long-Term Disability after Critical Illness
Authors: Taro Yasuma, Corina N. D’Alessandro-Gabazza, Osamu Hataji, Tetsu Kobayashi, Esteban C. Gabazza
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

We read with great interest the article by Brummel and colleagues regarding the role of inflammation and coagulation on long-term cognitive impairment and disability in patients with a critical illness (1).We congratulate the authors for their excellent work.Although the study provided solid evidence ruling out the influence of systemic inflammation on subsequent cognitive impairment and disability, the implications of activation of the coagulation system remain unclear.No direct markers of clotting activation were evaluated.Instead, the level of protein C, the zymogen precursor of activated protein C, was used as a marker of coagulation activation, as its circulating level is commonly decreased in systemic inflammation-associated prothrombotic states owing to its increased conversion to activated protein C (2, 3).However, it is unclear whether the levels of protein C were decreased in the population included in the study.Furthermore, besides its anticoagulant function, the beneficial effects of activated protein C under critically ill conditions (e.g., sepsis) are also attributed to its antiinflammatory, cytoprotective, and antiapoptotic activities that are mediated by the epithelial protein C receptor-dependent cleavage of the protease-activated receptor-1 (4, 5).Significant antiinflammatory actions of activated protein C include the suppression of the neutrophil extracellular trap formation, reduction of cytokine release from inflammatory cells, and protection of the endothelial barrier function (4-6).The insufficient information on the levels of protein C and the well-recognized anticoagulation-independent properties of protein C call into question whether protein C level was an appropriate marker for coagulation activation in the study.Circulating levels of more direct markers of coagulation system activation (e.g., D-dimer, activated factor V, or thrombin-antithrombin complex) would provide more informative results.On this basis, we believe that the data reported in the study are insufficient to rule out the effects of activation of the coagulation system on long-term disability after critical illness.
Risk Factors Associated With COVID-19 Outcomes Among People With Intellectual and Developmental Disabilities Receiving Residential Services
Authors: Scott D. Landes, Margaret A. Turk, Marco R. Damiani, Philip Proctor, Sarah Baier
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Although there is evidence of more severe COVID-19 outcomes, there is no information describing the risk factors for COVID-19 diagnosis and/or mortality among people with intellectual and developmental disabilities (IDD) receiving residential support services in the US. <h3>Objective</h3> To identify associations between demographic characteristics, residential characteristics, and/or preexisting health conditions and COVID-19 diagnosis and mortality for people with IDD receiving residential support services. <h3>Design, Setting, and Participants</h3> This cohort study tracked COVID-19 outcomes for 543 individuals with IDD. Participants were receiving support services from a single organization providing residential services in the 5 boroughs of New York City from March 1 to October 1, 2020. Statistical analysis was performed from December 2020 to February 2021. <h3>Exposures</h3> Resident-level characteristics, including age, sex, race/ethnicity, disability status, residential characteristics, and preexisting medical conditions. <h3>Main Outcomes and Measures</h3> COVID-19 diagnosis was confirmed by laboratory test. COVID-19 mortality indicated that the individual died from COVID-19 during the course of the study. Logistic regression models were used to evaluate associations between demographic characteristics, residential characteristics, and preexisting health conditions and COVID-19 diagnosis and mortality. <h3>Results</h3> Among the 543 individuals with IDD in the study, the median (interquartile range) age was 57.0 (45-65) years; 217 (40.0%) were female, and 274 (50.5%) were Black, Asian/Pacific Islander, American Indian or Alaskan Native, or Hispanic. The case rate was 16 759 (95% CI, 13 853-20 131) per 100 000; the mortality rate was 6446 (95% CI, 4671-8832) per 100 000; and the case-fatality rate was 38.5% (95% CI, 29.1%-48.7%). Increased age (odds ratio [OR], 1.04; 95% CI, 1.02-1.06), Down syndrome (OR, 2.91; 95% CI, 1.49-5.69), an increased number of residents (OR, 1.07; 95% CI, 1.00-1.14), and chronic kidney disease (OR, 4.17; 95% CI, 1.90-9.15) were associated with COVID-19 diagnosis. Heart disease (OR, 10.60; 95% CI, 2.68-41.90) was associated with COVID-19 mortality. <h3>Conclusions and Relevance</h3> This study found that, similar to the general population, increased age and preexisting health conditions were associated with COVID-19 outcomes for people with IDD receiving residential support services in New York City. As with older adults living in nursing homes, number of residents was also associated with more severe COVID-19 outcomes. Unique to people with IDD was an increased risk of COVID-19 diagnosis for people with Down syndrome.
Improving the prediction of surgical outcome at secondary cytoreduction in patients with ovarian cancer: Results from retrospective part of HELP-ER study NOGGO TR2/ENGOT OV47-TR.
Authors: Ioana Braicu, Wanja Nikolai Kassuhn, Hagen Kulbe, Pauline Wimberger, Cagatay Taskiran, Klaus Pietzner, Alexander Mustea, Robert Armbrust, J.P. P. Grabowski, Felix Schmidt, Ali Ayhan, Carmen Rosa Beteta, Christina Fotopoulou, Jalid Sehouli
Journal: Journal of Clinical Oncology (2021)

5558 Background: Complete resection at secondary cytoreductive surgery is associated with prolonged progression free and overall survival for patients with relapsed ovarian cancer. Secondary cytoreductive surgery has no impact on survival rates, if macroscopically tumor clearance cannot be achieved. Therefore, in order to avoid unnecessary perioperative morbidity and mortality, selection of patients who will undergo secondary tumor debulking is crucial. This study aims to improve upon the contemporary Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score by including additional clinical variables like circulating HE4 and CA125 levels to predict surgical outcome at secondary cytoreduction. Methods: A total of 90 patients underwent secondary cytoreductive surgery and were retrospectively assigned a positive AGO score. Of those patients, 62 (68.9%) achieved optimal surgical outcome at secondary debulking with 28 (31.1%) patients retaining residual tumor mass ( &gt; 0mm). Utilizing clinical variables including circulating HE4 and CA125 levels, we implemented a machine learning workflow to predict suboptimal surgical outcome in patients despite a positive AGO score. Results: We elucidated significantly lower levels of circulating HE4 (p = 0.0038) in patients with optimal surgical outcome compared to patients that retain macroscopic residual tumor at secondary cytoreductive surgery. Moreover, machine learning algorithms trained on clinical variables (e.g. serum HE4 level, serum CA125 level, age, Risk of Ovarian Malignancy Algorithmus (ROMA) score and occurrence of peritoneal carcinomatosis) achieved a mean area under the curve (AUC) of 78.4% based on 100 consecutive executions with randomized training and test sets. Conclusions: The application of machine learning allows to further improve the prediction of patients with high likelihood of achieving optimal surgical outcome at secondary cytoreduction. In turn, it might identify patients that would benefit from amplified treatment efforts. However, machine learning relies on large amounts of data to account for biological and clinical variation and produce predictions of sufficient/adequate quality. Given this limitation, we would validate this data within the prospective multicentric cohort of patients collected within NOGGO/ENGOT HELP_ER Trial.
Mucin depleted foci (MDF) new biomarkers in colon carcinogenesis, are decreased by calorie-restriction and show alterations in mucin production similar to colorectal tumors.
Authors: Pietro Femia, Piero Dolara, Elena Tarquini, Maddalena Salvadori, Giovanna Caderni
Journal: Cancer Research (2007)

2583  Mucin depleted foci (MDF) are putative preneoplastic lesions identified in the colon of carcinogen-treated rats by our group (1). To obtain further data on the preneoplastic nature of MDF, we studied the correlation between MDF and colon carcinogenesis in F344 rats initiated with 1,2 dimethylhydrazine and treated with a calorie-restricted (CR) diet (70% of the calories consumed by Controls). CR, known to reduce colon cancer, also significantly reduced MDF (MDF/rat were 6.5 ±2.4 and 3.6±1.9 in Controls and CR, respectively, means±SD, P= 0.01). Moreover, to characterize MDF we tested with immunohistochemistry MUC2, a mucin abundantly expressed in normal colon and MUCA5C, a mucin up-regulated in colon carcinogenesis (2). MDF and tumours show a dramatic reduction in the expression of MUC2 (Labelling Index (LI): 1.5±2.5 (n=16), 0.9 ±0.8 (n=11), and 83.6 ±12 in MDF, tumours, and matched normal mucosa, respectively, means±SD). The results on MUC5AC expression showed that while the expression of this antigen is almost absent in normal mucosa (LI: 0.31±0.5, mean ±SD), it is significantly increased in MDF (LI: 7.4 ± 4.9, n= 13) as well in tumours (1.7±1.2, n=11). Lack of MUC2 has been related to colon cancer development (3) and abrogation of Wnt-signaling has been reported to up-regulates MUC2 (4). Since we previously demonstrated that MDF show upregulation of Wnt-signalling (5), it is possible that the depletion of MUC2 seen in these lesions is related to the activation of this pathway. Moreover, the fact that MDF, as well as tumours, do not express MUC2, and show an increase in MUC5AC suggest a similar molecular defect in these lesions and support the hypothesis that MDF are cancer precursors. Acknowledgements. We thank Dr. J. Bara (Hopital St-Antoine, Paris, France) for the generous gift of antibodies against MUC5AC. Supported by grant “ 05A019-REV” from the American Institute for Cancer Research, by AIRC (Italian Association for Cancer Research, Regional Grant) and by Fondo Ateneo ex-60% of the University of Florence.  References: 1) Caderni G et al.Cancer Res. 63: 2388-92, 2003. 2) Bara J et al., Tumour Biol. 24:109-15, 2003. 3) Velcich A et al.,. Science. 295: 1726-9, 2002. 4) van de Wetering et al., Cell. 111:241-50, 2002. 5) Femia AP et al., Int J Cancer, 116: 9-15, 2005.
Chemokines and eicosanoids fuel the hyperinflammation within the lungs of patients with severe COVID-19
Authors: Younes Zaid, Étienne Doré, Isabelle Dubuc, Anne-Sophie Archambault, Olivier Flamand, Michel Laviolette, Nicolas Flamand, Éric Boilard, Louis Flamand
Journal: Journal of Allergy and Clinical Immunology (2021)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to a variety of clinical outcomes, ranging from the absence of symptoms to severe acute respiratory disease and ultimately death. A feature of patients with severe coronavirus disease 2019 (COVID-19) is the abundance of inflammatory cytokines in the blood. Elevated levels of cytokines are predictive of infection severity and clinical outcome. In contrast, studies aimed at defining the driving forces behind the inflammation in lungs of subjects with severe COVID-19 remain scarce.Our aim was to analyze and compare the plasma and bronchoalveolar lavage (BAL) fluids of patients with severe COVID-19 (n = 45) for the presence of cytokines and lipid mediators of inflammation (LMIs).Cytokines were measured by using Luminex multiplex assay, and LMIs were measured by using liquid chromatography-tandem mass spectrometry.We revealed high concentrations of numerous cytokines, chemokines, and LMIs in the BAL fluid of patients with severe COVID-19. Of the 13 most abundant mediators in BAL fluid, 11 were chemokines, with CXCL1 and CXCL8 being 200 times more abundant than IL-6 and TNF-α. Eicosanoid levels were also elevated in the lungs of subjects with severe COVID-19. Consistent with the presence chemotactic molecules, BAL fluid samples were enriched for neutrophils, lymphocytes, and eosinophils. Inflammatory cytokines and LMIs in plasma showed limited correlations with those present in BAL fluid, arguing that circulating inflammatory molecules may not be a reliable proxy of the inflammation occurring in the lungs of patients with severe COVID-19.Our findings indicate that hyperinflammation of the lungs of patients with severe COVID-19 is fueled by excessive production of chemokines and eicosanoids. Therapeutic strategies to dampen inflammation in patients with COVID-19 should be tailored accordingly.
The genomic landscape of gene fusions across solid tumors and clinical outcome of targeted therapies: A real-world retrospective analysis.
Authors: Yumeng Zhang, Bindiya G Patel, Todd C Knepper, Dung-Tsa Chen, Jhanelle Elaine Gray, James Kevin Hicks
Journal: Journal of Clinical Oncology (2021)

3132 Background: Oncogenic gene fusions can be observed across numerous solid tumor types with therapies targeting fusion events emerging as important treatment modalities. The occurrence of rare fusion events and response to targeted therapy inclusive of off-label drug use has not been fully elucidated. We describe a real-world (RW) landscape of gene fusions in solid tumors and treatment outcomes of targeted therapies. Methods: Patients with solid tumors harboring a gene fusion or rearrangement were retrospectively identified through review of a clinical molecular database housing sequencing data on 6,800 patients from a single-center between 1/1/2015 – 12/31/2019. Patients who received targeted therapy for gene fusions were divided into three arms: off-label, on-label, and clinical trial use. Clinical characteristics were summarized using descriptive statistics. Overall survival (OS) and Progression free survival (PFS) between the three arms were compared using the Kaplan-Meier estimates. Results: A total of 336 (4.9%) patients had a fusion positive solid tumor with 197 (2.9%) having a fusion event predicted to be oncogenic and could be targeted with a drug. Thirty different cancer types had targetable fusions with the three most common types being lung adenocarcinoma (41%), glioblastoma (10.2%), and melanoma (7.1%). The most common observed targetable fusions included ALK (21.3%), RET (11.7%), ROS1 (9.1%), and FGFR2 (8.1%). A total of 71 patients received targeted therapy; 37 (52%) received therapies on-label, 20 (28%) off-label, and 14 (20%) on-trial (Table). The median PFS was 4 months for off-label, 16 months for on-label, and 9 months for on trial-therapy (p=0.02). The median OS was 8 months for off-label, 51 months for on-label, and 11 months for on-trial therapy (p=0.001). Seven out of twenty patients (35%) in the off-label group had PFS for at least 6 months. Three patients had a response for more than one year. However, higher toxicity related discontinuation rate was observed (30%, 8%, 7% for off-label, on-label, and on-trial, p=0.03). Conclusions: Off-label targeted therapy had shorter PFS and OS when compared to on-label therapy. However, 35% patients in the off-label group had at least 6 months PFS. Off-label therapy remained a valuable option for patients who were not candidate for clinical trials or with rare fusions. Further studies are needed to determine which patients are most likely to benefit from targeting gene fusion events.[Table: see text]
TRPV2-spike protein interaction mediates the entry of SARS-CoV-2 into macrophages in febrile conditions
Authors: Jinrui Xu, Yuquan Yang, Zhaoyuan Hou, Hao Jia, Yujiong Wang
Journal: Theranostics (2021)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel strain of highly contagious coronaviruses that infects humans.Prolonged fever, particularly that above 39.5 °C, is associated with SARS-CoV-2 infection.However, little is known about the pathological effects of fever caused by SARS-CoV-2.Methods: Primary bovine alveolar macrophages (PBAMs), RAW264.7 mouse macrophages, and THP-1 human cells were transfected with plasmids carrying the genes encoding the SARS-CoV-2 spike (S) protein or receptor-binding domain (RBD).Proteins in the macrophages interacting with S-RBD at 39.5 °C or 37 °C were identified by immunoprecipitation-mass spectrometry.Glutathione S-transferase pulldown, surface plasmon resonance, and immunofluorescence were performed to evaluate the transient receptor potential vanilloid 2 (TRPV2) interaction with SARS-CoV-2-S-RBD at 39.5 °C.Using an RNA sequencing-based approach, cytokine gene expression induced by SARS-CoV-2 S transfection at 39.5 °C and 37.5 °C in primary alveolar macrophages was measured.Fluo-4 staining and enzyme-linked immunosorbent assays were used to assess the regulatory function of TRPV2 in intracellular Ca 2+ and cytokines under SARS-CoV-2-S-RBD at 39.5 °C.Additionally, cytokine release was examined after TRPV2 knockdown with shRNA oligonucleotides or inhibition using the SKF-96365 antagonist. Results:We identified an interaction between the primary alveolar macrophage receptor TRPV2 and S-RBD under febrile conditions.Febrile temperature promotes Ca 2+ influx through SARS-CoV-2 infection in PBAMs, further activates the NF-κB p65 signaling pathway, and enhances the secretion of cytokines.Furthermore, knockdown or antagonist (with SKF-96365) of TRPV2 significantly decreased the release of cytokines that drive the inflammatory response.Conclusion: Collectively, our findings identified TRPV2 as a receptor of SARS-CoV-2 in conditions of febrile temperature, providing insight into critical interactions of SARS-CoV-2 with macrophages, as well as a useful resource and potential drug target for coronavirus disease 2019.
Successful allografting for relapsing pediatric ALL: The results of two decades.
Authors: O. Bulent Zulfikar, Basak Koc
Journal: Journal of Clinical Oncology (2021)

e22000 Background: The prognosis of children and adolescents with acute lymphoblastic leukemia (ALL) has dramatically improved. This success is associated with both by multiagent chemotherapy regimens and by definition of clinical, biological and treatment response that allow the administration of risk-adapted therapy, including allogeneic hematopoietic stem cell transplantation (HSCT). In treatment of relapsed and resistance ALL, allogeneic HSCT continues to play a major curative role. In the present study, we desciribed the patients who underwent HSCT in our clinic in the last 21 years. Methods: From 1999 to 2020, 147 patients who diagnosed with ALL and treated with the COG protocols at the Istanbul University Oncology Institute were retrospectively reviewed and 17 of them relapsed. HSCT was applied 7 of the relapsed cases and also 3 resistant cases who had suitable matched donors. The demographic features, laboratory findings and treatment responses of 10 patients were recorded from the patients’ medical records. Results: All 10 patients were B-ALL with median diagnosis age of 79.5 months (range: 32-195) and 5 were male. Characteristics of patients given in Table 1. HSCT was performed due to late relaps in 7 patients. Three of the 7 relaps were only bone marrow and other 4 had combined. Patient #2 had both breast, conjunctiva and bone marrow for the 1st relaps and only conjunctiva for the 2nd one and this patient had also t(9;22) in the 1st relaps. Patient #3 had bone marrow+central nervous system relaps and patient #7 had bone marrow for the 1st relaps and testis and bone marrow for the 2nd one. Other 3 had poor response to treatment and Minimal Residual Disease (MRD) was high in End of Introduction (EoI) and End of Consolidation (EoC)). All patients had allogeneic HSCT and 8 are alive. Conclusions: HSCT remains the standard-of-care treatment for ALL patients who carry high-risk features predicting leukemia recurrence and for those experiencing high-risk first relapse or multiple relapses. Additionally, defining the indications of HSCT are dynamic and it could change according to treatment options as well as new molecular and biological findings. It is important to identify the patients who have high relapse risk and HSCT should have priority in patients whom MRD is high in EoI and EoC.[Table: see text]
ENSURE: An international multicenter study exploring whether surveillance after esophageal cancer surgery impacts oncological and quality-of-life outcomes.
Authors: Jessie A Elliott, Sheraz Markar, Fredrik Klevebro, Asif Johar, Lucas Goense, Maeve Aine Lowery, Pernilla Lagergren, Giovanni Zaninotto, Richard van Hillegersberg, Magnus Nilsson, George Hanna, John V. Reynolds
Journal: Journal of Clinical Oncology (2021)

4032 Background: Although established and emerging therapies for recurrent esophageal cancer (EC) may impact on survival and health related quality of life (HRQL), surveillance protocols after the primary curative treatment of EC are varied and inconsistent, reflecting a limited evidence-base to guide an optimum approach. Specifically, whether advantages exist for an intensive surveillance protocol is unknown and was the focus of this study. Methods: European iNvestigation of SUrveillance after Resection for Esophageal cancer (ENSURE) is an international multicenter retrospective observational study of consecutive patients undergoing surgery with curative intent for esophageal and gastroesophageal junction cancers (2009 – 2015) across 20 European and North American cancer centers (NCT03461341). Intensive surveillance (IS) was defined as routine annual CT/PET-CT along with clinical assessment during the first three postoperative years, and compared with standard surveillance (SS) with investigation as clinically indicated. The primary outcome measure was overall survival (OS), secondary outcomes included treatment administered, disease-specific survival (DSS), disease-free survival (DFS), recurrence pattern, and HRQL. Multivariable linear, logistic and Cox proportional hazards regression analyses were performed to determine the independent impact of surveillance on oncologic outcomes and HRQL. Results: 4,682 patients were studied (72.6% adenocarcinoma, 69.1% neoadjuvant therapy). 45.5% underwent IS. At a median follow-up of 60 months, 47.5% developed disease recurrence. Oligometastatic recurrence occurred in 39% of cases, with 31% receiving best supportive care, 60% chemotherapy and/or radiation, and 8% surgical resection. IS was associated with reduced symptomatic recurrence (odds ratio [OR] 0.17 [0.12–0.25]), increased tumor-directed therapy (OR 2.09 [1.58–2.77]), and improved OS (HR 0.90 [0.82–0.98], 5-year OS 47.9±1.2% versus 43.2±1.1%). After adjusting for confounders, significantly improved overall survival with IS was maintained for patients who underwent surgery alone as initial therapy (HR 0.60 [0.47–0.78]) and in those with lower pathological (y)pT stages (Tis-2, HR 0.72 [0.58–0.89]). IS was associated with greater anxiety ( P= 0.016), but similar overall HRQL. Conclusions: These data suggest that IS may improve oncologic outcomes, particularly in patients with early stage disease at presentation or with a favorable pathological stage post induction therapy. This may be relevant to guideline development and provide a framework and rationale for RCTs. It may also inform shared decision-making with patients at a time where therapeutic options for recurrence are expanding.