tbuckley/cabot-search huggingface dataset:
Correlation of E- and N-cadherin expressions as a prognostic factor in metastatic and nonmetastatic gastric tumors.
Authors: Elena P. Ulianova, Aleksandr B. Sagakyants, Inna A. Novikova, Evgeniya M. Nepomnyashchaya, Elena N. Chernikova, Svetlana M. Bakulina, Tatiana F. Pushkareva, Elena A. Dzhenkova, Aleksandr V. Shaposhnikov, Evgeniy N. Kolesnikov
Journal: Journal of Clinical Oncology (2021)

e16028 Background: Over the past 10 years, gastric cancer has been in the top five most common malignant tumors with a high mortality rate. Its poor prognosis is determined by the aggressive disease course with the development of distant metastases. Additional markers of tumor progression are required, and a special role in tumor progression is assigned to the epithelial-mesenchymal transition (EMT). E- and N-cadherins are among the key EMT regulators. Our purpose was to reveal possible prognostic value of EMT markers in different forms of gastric cancer. Methods: The study included patients (aged 30-80 years) with gastric cancer: control group (n = 20, 58.9±9.7 years) – non-metastatic gastric cancer T3-4аN0-3M0 (G2); main group (n = 20, 53.4±11.9 years) – gastric cancer T3-4аN0-3M1 (G2) with peritoneal metastases. IHC analysis was performed on sections from paraffin tumor blocks using mouse monoclonal antibodies to E-cadherin (SMP471, Diagnostic BioSystems) and N-cadherin (SP90, Spring Bioscience) diluted 1:30, and the Reveal Polyvalent HRP-DAB Detection System. Expression of E- and N-cadherins was analyzed semi-quantitatively according to the percentage of cells showing membrane positivity and the intensity of staining: 0 (from 0 to 10%); 1+ (from 11 to 30%); 2+ (from 31 to 70%); 3+ ( &gt; 70%). Expression was considered positive in ≥2. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA) using the Pearson's chi-square test and the Spearman's correlation. Results: Maximal staining for E-cadherin was observed in the control group (in 90%), staining for N-cadherin – in the main group (in 70%). Average expressions of E- and N-cadherins were: in controls – 34.5±4.5 and 24.1±5.7; in the main group – 24.6±5.8 and 28.3±4.3. The Pearson's test showed the statistically significant prevalence of patients with E-cadherin+ tumors in the control group (7.619, p = 0.006), and the prevalence of patients with N-cadherin+ tumors in the main group (4.912, p = 0.027). However, when considering the correlation between E-cadherin and N-cadherin in the groups, the Spearman's correlation was not statistically significant (rs = -0.342 in the control group and rs = -0.430 in the main group at p &gt; 0.05). Conclusions: The study revealed only a tendency towards the loss of E-cadherin and increased expression of N-cadherin, which is often associated with a poor prognosis. However, a more extensive study is required to assess the possible prognostic value of these EMT markers in metastatic and non-metastatic gastric cancer.
Preclinical monotherapeutic and anti-PD-1 synergistic anti-tumor efficacy of MNC-168, a novel human-derived live biotherapeutic product.
Authors: Chuan-Sheng Lin, Xianzhi Jiang, Baoxia Li, Yibo Xian, Xue Su, Zhenzhen Liu, Jiening Liang, Yingying Zhao, Qianying Deng, Baojia Huang, Tengxun Zhang, Ruijuan Zhu, Yajun Liang, Zhengjiao Liang, Chen Xiao, Zupeng Kuang, Guozhen Zhao
Journal: Journal of Clinical Oncology (2021)

e14581 Background: Human gut microbiome has been extensively demonstrated as a critical causative factor in determining the efficacy of cancer immunotherapy. Cumulative clinical evidences indicate the prevalent presence of Enterococcus species in the responder of anti-PD-1 treated patients. We here demonstrated the preclinical anti-tumor efficacy of a novel human derived Enterococcus strain MNC-168. Methods: Using multiple murine syngeneic cold tumor models and in vivo pharmacokinetics mouse model, we characterized the anti-tumor activity and pharmacokinetics of MNC-168 via oral-delivered route in monotherapy and immune checkpoint inhibitor (ICI) anti-mPD-1 combination. Systematic multi-omics analyses and in vitro mechanistic study were conducted to reveal the biomarkers and mode of action of MNC-168. Results: We found MNC-168 significantly and mono-therapeutically counteract tumor development in diverse tumor models, including colorectal cancer (with tumor inhibition ratio of 65.5%), hepatocellular carcinoma (27.4%), fibrosarcoma (33.5%) and renal carcinoma (56.4%). Notably, MNC-168 in combination with anti-mPD-1 synergistically exerted the tumor inhibition ratio up to 68.3-89.2% and significantly reverse anti-mPD-1 non-responsiveness. Integrated multi-omics analyses and in vitro validation study revealed the mechanism by which MNC-168 reinvigorates the immune system through targeting multiple routes, including activating systemic and tumor-resident innate and adaptive immunity, removal of tumor physical barrier, reinforced recruitment of tumor-infiltrating lymphocytes, and maintenance of immuno-stimulant activity via production of immune-simulating metabolites. Activation and boosting of interferon-γ production of CD8 T cells and CD4 T cells are the vital mediators for the anti-tumor ability of MNC-168. In vivo pharmacokinetics study shows that the anti-tumor efficacy of MNC-168 is positively correlated with gut-restricted abundance of MNC-168. Conclusions: MNC-168 is highly potently used as a first-in-class live biotherapeutic product for cancer monotherapy and promoting efficacy of ICI-mediated cancer immunotherapy.
Pericardial disease in patients treated with immune checkpoint inhibitors
Authors: Jingyi Gong, Zsofia Dora Drobni, Amna Zafar, Thiago Quinaglia, Sarah Hartmann, Hannah K Gilman, Vineet K Raghu, Carlos Gongora, Meghan E Sise, Raza M Alvi, Leyre Zubiri, Anju Nohria, Ryan Sullivan, Kerry L Reynolds, Daniel Zlotoff, Tomas G Neilan
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background There are limited data on the occurrence, associations and outcomes of pericardial effusions and pericarditis on or after treatment with immune checkpoint inhibitors (ICIs). Methods This was a retrospective study at a single academic center that compared 2842 consecutive patients who received ICIs with 2699 age- and cancer-type matched patients with metastatic disease who did not receive ICI. A pericardial event was defined as a composite outcome of pericarditis and new or worsening moderate or large pericardial effusion. The endpoints were obtained through chart review and were blindly adjudicated. To identify risk factors associated with a pericardial event, we compared patients who developed an event on an ICI with patients treated with an ICI who did not develop a pericardial event. Cox proportional-hazard model and logistical regression analysis were performed to study the association between ICI use and pericardial disease as well as pericardial disease and mortality. An additional 6-week landmark analysis was performed to account for lead-time bias. Results There were 42 pericardial events in the patients treated with ICI (n=2842) over 193 days (IQR: 64–411), yielding an incidence rate of 1.57 events per 100 person-years. There was a more than fourfold increase in risk of pericarditis or a pericardial effusion among patients on an ICI compared with controls not treated with ICI after adjusting for potential confounders (HR 4.37, 95% CI 2.09 to 9.14, p&lt;0.001). Patients who developed pericardial disease while on an ICI had a trend for increased all-cause mortality compared with patients who did not develop a pericardial event (HR 1.53, 95% CI 0.99 to 2.36, p=0.05). When comparing those who developed pericardial disease after ICI treatment with those who did not, a higher dose of corticosteroid pre-ICI (&gt;0.7 mg/kg prednisone) was associated with increased risk of pericardial disease (HR 2.56, 95% CI 1.00 to 6.57, p=0.049). Conclusions ICI use was associated with an increased risk of development of pericardial disease among patients with cancer and a pericardial event on an ICI was associated with a trend towards increase in mortality.
Hypoattenuated Leaflet Thickening After Transcatheter Pulmonary Valve Replacement With the SAPIEN 3 Valve
Authors: Muhammad Hammadah, B. Kelly Han, Mariana de Oliveira Nunes, Jamil A. Aboulhosn, Evan M. Zahn, Vasilis Babaliaros, Matthew J. Daniels, João L. Cavalcante, John R. Lesser, Santiago Garcia
Journal: JACC. Cardiovascular imaging (2021)
Abstract 270: Peroxisome Proliferator Activated Receptor- α is a Connecting Link Between Cardiac Fibrosis and Oxidative Stress in Atrial Fibrillation
Authors: Farhan Rizvi, Larisa Emelyanova, Stacie Edwards, Breanna Aldred, Peter Homer, David Kress, Gracious Ross, Jasbir Sra, A. Jamil Tajik, Arshad Jahangir
Journal: Circulation Research (2017)

Background: AF, a common sustained arrhythmia that predisposes heart failure and stroke, is associated with cardiac fibrosis and oxidative stress. Peroxisome proliferator-activated receptor (PPAR)-α, important for ROS and lipid degradation, is reported to negatively correlate with kidney, liver, and lung fibrosis, but its role in cardiac fibrosis is less clear. We hypothesize that reduced expression of PPARα in AF contributes to oxidative stress and interferes with TGFβ signaling, a cytokine implicated in cardiac fibrosis. Methods: Myocardial fibrosis was detected (Masson trichrome) in right atrial appendages of AF and non-AF patients. Levels of 4-hydroxynonenal (4-HNE) (ELISA) and superoxide production (MitoSOX) were assayed in patients’ atrial tissue homogenates and cardiac myofibers respectively. Using atrial fibroblasts (hAF) from AF and non-AF patients, α-SMA, COL1A1 and c-Jun/c-Fos expressions were determined (RT-PCR and/or Western Blot) in the absence and presence of TGF-β (5 ng) with or without ciprofibrate (200 μM), a PPARα agonist. Results: Increased atrial fibrosis, levels of 4-HNE (101.7 vs 7.4 ng/mg protein; p=0.02(n=6)) and oxidative stress (8.7 fold; p=0.04) correlated with reduced PPAR-α mRNA (2.1 fold; p&lt;0.01) in AF patients. Activation of PPARα by ciprofibrate reduced TGFβ1-induced increased expression of α-SMA and COL1A1 by repressing AP-1 signaling in hAF. Conclusion: Reduced expression of PPARα is associated with impaired cardiac mitochondrial metabolism and promotes TGFβ-induced profibrotic pathway. Preliminary data suggest PPARα agonist might confer therapeutic benefits for patients with cardiac fibrosis and oxidative stress in AF.
Metabolic and bariatric surgery among endometrial cancer survivors: Are we missing an opportunity to help?
Authors: Justin Gray, Ajay A Myneni, Lorin M Towle-Miller, Iman Simmonds, Matthew Burnstein, Steven Schwaitzberg, Aaron B Hoffman, Emese Zsiros, Katia Noyes
Journal: Journal of Clinical Oncology (2021)

5591 Background: Multiple studies have delineated a clear link between the estrogenic effects of obesity and the incidence of endometrial cancer (EC). Obese EC patients are less likely to receive guideline-recommended surgical treatment (ST) relying instead on chemotherapy and radiation therapy. Furthermore, EC patients are more likely to die from obesity-related complications than from cancer-related causes. Several small-scale studies have demonstrated that metabolic and bariatric surgery (MBS) could offer EC patients fast, safe and effective weight loss, which provides an opportunity to improve survival. This is the first population-based study that examines uptake and outcomes of MBS among EC survivors in New York State (NYS). Methods: This study was based on the all-payer longitudinal data from the NYS’s Statewide Planning and Research Cooperative System and included inpatient and ambulatory surgeries performed between 2006 and 2012. Using ICD and CPT diagnostic and procedure codes, we identified patients diagnosed with EC for the first time, and we further examined whether they received ST within one year of their initial EC diagnosis. We followed EC patients with ST for 4 years to examine the rates of MBS, and we assessed long-term patient outcomes through 2019. We conducted bivariate and multivariate analyses to evaluate all-cause mortality and identify risk factors for poor surgical outcomes and readmissions. Results: Among 24,950 EC patients (2006-2012), 16,156 (65%) of them underwent ST within 1 year of EC diagnosis. Compared to those who did not receive ST, patients who underwent ST were younger, less likely to be White and more likely to be from urban counties, had private insurance, diagnosed with diabetes and hypertension, and had lower Elixhauser scores for readmission and mortality ( p &lt; 0.01 for all). Within 4 years following ST, 136 (0.8%) EC patients underwent MBS. Those who underwent MBS were younger ( p &lt; 0.01), predominantly white, privately insured, morbidly obese ( p &lt; 0.01) and diabetic ( p = 0.01) compared to those who did not undergo MBS. Conclusions: Despite having higher risk of mortality from obesity-related complications such as diabetes and cardiovascular disease, the proportion of EC patients obtaining MBS (0.8%) was similar to that seen among the US population eligible for MBS (1.0%). More research is needed to understand barriers to MBS among eligible women with EC.
Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis, and rescue by IL-21
Authors: SuJin Hwang, Christina Tatsi, Hye Sun Kuehn, Julie E Niemela, Jennifer Stoddard, Yan Su, Maya Lodish, Gulbu Uzel, Rosanne Spolski, Warren J Leonard, Steven M Holland, Thomas A Fleisher, Constantine A Stratakis, Sergio D Rosenzweig
Journal: Journal of Allergy and Clinical Immunology (2021)
Impact of the VA opioid safety initiative on pain management for cancer patients.
Authors: Mallika Marar, Vinit Nalawade, Neil Panjwani, Paul Riviere, Timothy Furnish, Lewei A. Lin, Reid F. Thompson, James Don Murphy, Lucas K. Vitzthum
Journal: Journal of Clinical Oncology (2021)

102 Background: Limited research exists on how risk reduction policies in response to the opioid epidemic have impacted pain management among cancer patients. This study investigated the impact of the Veteran’s Health Administration (VHA) Opioid Safety Initiative (OSI) on opioid prescribing patterns and opioid-related toxicity among patients undergoing definitive cancer treatment. Methods: This retrospective cohort study included 42,064 opioid-naïve patients receiving definitive local therapy for prostate, lung, breast, and colorectal cancer at the VHA from 2011-2016. Interrupted time series analysis with segmented regression was used to evaluate the impact of the OSI, which launched October 2013. The primary outcome was the incidence of new opioid prescriptions with diagnosis or treatment. Secondary outcomes included rates of high daily dose opioid (≥ 100 morphine milligram equivalent) and concomitant benzodiazepine prescriptions. Additional long-term outcomes included persistent opioid use, opioid abuse diagnoses, pain-related ED visits, and opioid-related admissions. Results: Prior to OSI implementation, the incidence of opioid prescriptions among new cancer patients increased from 26.7% (95% CI 25.0 – 28.4) in the first quarter (Q1) of 2011 to 50.6% (95% CI 48.3 – 53.0) in Q3 2013. There was a monthly increase in opioid prescription rate pre-OSI followed by a monthly decrease post-OSI (Table). High-dose opioid prescriptions were rare, and the monthly rate was stable before and after the OSI. Monthly incidence of concomitant benzodiazepine prescriptions was stable pre-OSI and decreased post-OSI. Persistent opioid use increased pre-OSI and decreased post-OSI. Pain-related ED visits had an incidence of 0.8% (95% CI 0.4 – 1.0) in Q1 2011, 0.3% (95% CI 0.1 – 0.6) in Q3 2013, and 1.8% (95% CI 0.9 – 2.7) in Q4 2016, with an increasing monthly rate after the OSI. At three years, the cumulative incidence of opioid abuse was 1.2% for both the pre- and post-OSI groups but opioid-related admissions were greater in the pre-OSI cohort than the post-OSI cohort (0.9% vs. 0.5%, p &lt; 0.001). Conclusions: The OSI was associated with a decrease in new, persistent, and certain high-risk opioid prescribing as well as an increase in pain-related ED visits. Further research on patient-centered outcomes is required to optimize opioid prescribing policies for patients with cancer.[Table: see text]
The efficacy and safety of oral levofloxacin therapy for overall infection prophylaxis in cancer patients with neutropenia in outpatient settings.
Authors: Lilia Davenport, Jamie Chin, Sharon Blum, Meredith Akerman
Journal: Journal of Clinical Oncology (2021)

e18681 Background: Patients undergoing chemotherapy treatment are at risk for bacterial infection during their period of neutropenia. However, not all neutropenic patients are at high risk for developing infection. The purpose of this study was to evaluate the efficacy and safety of prophylactic oral levofloxacin in high, intermediate, and low infection risk patients with cancer in the ambulatory care setting. Methods: This was a retrospective chart review of 100 cancer patients with high, intermediate, and low overall infection risk who were prescribed outpatient oral levofloxacin prophylaxis between October 2019 and July 2020. This quality improvement project included adults with a history of malignancy and presence of neutropenia who have received chemotherapy treatment and oral levofloxacin therapy for overall infection prophylaxis. The primary efficacy outcome was the rate of hospital admission due to febrile neutropenia. The primary safety outcome was the occurrence of side effects of levofloxacin therapy. Secondary outcomes evaluated the duration of levofloxacin therapy, the rate of fluoroquinolone resistance in positive bacterial cultures, progression to sepsis in hospitalized patients and the rate of death due to mult-idrug resistance including fluoroquinolones. Results: Hospital admission due to febrile neutropenia after a chemotherapy cycle occurred in 18% of patients prescribed levofloxacin. Among hospitalized patients due to febrile neutropenia, 2% had low to intermediate overall infection risk and 16% had high overall infection risk. The primary safety outcome occurred in 25% of patients. The incidence of QTc prolongation occurred in 8% of patients; dermatologic side effects occurred in 9% of patients; the rate of Clostridioides difficile infection was 6%, and the rate of tendon rupture was 2%. Median duration of levofloxacin prophylaxis in the low overall infection risk group was 7 days, compared to the intermediate overall infection risk group (8.5 days) and the high overall infection risk group (14 days) with Kruskal-Wallis test p-value of 0.0009. The rate of fluoroquinolone resistance in positive bacterial cultures was 10%. Progression to sepsis in hospitalized patients occurred in 17% of patients. The rate of death due to multi-drug resistance including fluoroquinolone was 2%. Conclusions: Our findings signify preserved efficacy of levofloxacin prophylaxis in the ambulatory setting. Our findings should be considered to develop rational strategies to reduce fluoroquinolone overprescribing or limit duration of levofloxacin prophylaxis. If patients present with solid tumors and experience neutropenia, the use of antibacterial prophylaxis is not recommended because in general, patients recover from neutropenia quickly.
Parotid sparing adaptive radiotherapy in head and neck cancer patients: A study evaluating resource intensiveness and impact on quality of life.
Authors: Shaurav Maulik, Indranil Mallick, Moses Arunsingh, Sriram Prasath, B Arun, Sanjoy Chatterjee
Journal: Journal of Clinical Oncology (2021)

e24037 Background: Anatomical changes during the course of parotid sparing IMRT for head and neck cancer can lead to an increase in the actual dose absorbed by the parotid glands, which may be controlled with the use of interval adaptive replanning. In this prospective assessment of adaptive replanning for parotid dose changes, we explored the feasibility of carrying out adaptive replanning based on predefined objective dosimetric criteria at specified time points. We sought to assess the impact of this measure using a clinically meaningful endpoint of patient reported quality of life outcomes. Methods: 90 patients with head and neck radiotherapy indicated for definitive management or adjuvant therapy who had at least one parotid gland receiving a mean dose (MD) of between 25-30Gy were accrued in the study. The index parotid was delineated on the images acquired on 14th and 19th day and the MD was determined by overlaying the verification image on the planned CT. If the MD had increased by 2% of the initial intended dose, an adaptive plan was attempted with an aim to reduce MD by 2% without compromising PTV coverage; this plan was then used to deliver the remaining treatment. Patients were invited to complete QoL questionnaires: EORTC-QLQC30 with HN35 module, and XeQoL score at baseline, at 3 and 9 months after completion of treatment. Results: 46 out of 90 patients met the threshold for adaptive replanning and were switched to the new plan during treatment. Adaptive replanning was triggered at D14 for 31 patients and D19 for the remaining 15. Need for adaptive replanning was associated with receipt of concurrent chemotherapy and weight loss in the first two weeks of RT. QoL was evaluable for 50 patients at 3 months post treatment. In patients who required adaptive replanning per protocol, Mean XeQoL scores at 3 months showed significantly worse scores for overall scores (1.1 vs 2.3, p 0.001) and for the component individual physical, pain, psychological, and social domains. EORTC QLQ-C30 and HN35 questionnaires at 3 months also demonstrated significantly worse mean symptom scores of the relevant domains of mouth dryness (39 vs 60), stickiness (32 vs 54) and swallowing (39 vs 60) in patients who required adaptive replanning versus those who did not. No significant QoL trends were observable in the 31 patients who were evaluable at 9 months post treatment. The average time required for each step in the planning process was comparable for both the initial planning workflow and adaptive replanning process. Conclusions: The trigger criteria for replanning identified a population of patients who have significantly worsened quality of life due to radiation induced xerostomia. The benefits of adaptive replanning strategies based on weekly evaluation, binary thresholds and standard planning procedures is doubtful Clinical trial information: CTRI/2017/11/010683.
German doctors vote to prescribe heroin to misusers
Authors: D Cooper-Mahkorn
Journal: BMJ (1998)

Heroin should be distributed to a select group of longstanding addicts, the German Medical Council unanimously decided last week. The council has now applied to the minister of justice to enable opiates to be legalised in a strictly medically controlled context.

Dr Ingo Flenker, a member of the German Medical Council, said that the decision had been influenced by the recent results from Switzerland that showed the effectiveness of such an approach. Several other countries, including Australia, Denmark, …