tbuckley/cabot-search huggingface dataset:
Schlafen 11 (SLFN11), a putative predictive biomarker of platinum/PARPi response, is frequently detected on circulating tumor cells (CTCs) in advanced prostate cancer.
Authors: Howard I. Scher, Luisa Fernandez, Kate Cunningham, Natalie Elphick, Ethan Barnett, Jerry Lee, Cole Gilbertson, Emily Carbone, David Bourdon, Martin Blankfard, Eva Wang, Joshua Timothy Jones, Alisa Tubbs, Amanda Anderson, Joseph D. Schonhoft, Rick Wenstrup
Journal: Journal of Clinical Oncology (2021)

e17039 Background: Schlafen 11 (SLFN11) is a DNA repair protein (DNA/RNA helicase homology) that is recruited to stressed replication forks and leads to cell death. Recent ph II trial data in Extensive Stage Small-Cell Lung Cancer (ES-SCLC) [Byers et al. JCO 2018 PMID: 29906251] and a retrospective analysis of Circulating Tumor Cells (CTCs) and tumor tissue in patients (Pts) with advanced prostate cancer [Conteduca et al. Mol Cancer Therapeutics 2020 PMID: 32127465] suggested that SLFN11 expression predicts sensitivity to DNA damage targeting agents. In both contexts, metastatic tumor biopsies may not provide adequate material for profiling. We assessed the frequency of SLFN11 expression in CTCs isolated from blood in men with progressing metastatic Castration Resistant Prostate Cancer (mCRPC) and related expression to Homologous Recombination Repair (HRR) alterations identified in metastatic tumor biopsies profiled by MSK-IMPACT. Methods: 95 patients with progressing mCRPC about to start a new systemic therapy who had undergone pre-treatment metastatic tumor profiling by MSK-IMPACT and a matched blood draw for CTC profiling were selected. Blood was sent overnight to Epic Sciences and processed onto glass pathology slides and bio-banked until analysis. Detected CTCs (cytokeratin (CK) positive and leukocyte (CD45) negative) were analyzed for SLFN11 protein expression by immunofluorescence and correlated to Homologous Recombination Repair (HRR) alterations in metastatic biopsy from the bone, lymph node, or visceral metastases (15 PROFOUND genes). A mean of 1.2 mL of blood was analyzed per patient. Results: CTCs with SLFN11 expression (DAPI+, CK+, CD45-, SLFN11+) were detected in 28.4% (27/95) of the patient sample analyzed. SLFN11 signal was found to overlap with the nuclear DAPI signal. Individual CTC expression of SLFN11 in a sample was heterogeneous and ranged from a minimum of 2.9% to 100%. Seven of 10 (70%) of patients with a BRCA1/2 or ATM alteration had a least one SLFN11 expressing CTC. In contrast, in patients with other HRR alterations, only 20% (1/5) had CTCs with SLFN11. Sequencing of single CTCs is ongoing. Conclusions: SLFN11 expression is detected with high frequency in CTCs in men with progressing mCRPC. In whom CTCs are detected, the majority of patients with BRCA1/2 or ATM altered tumors also had SLFN11 expressing CTCs. The results support the prospective evaluation of CTC SLFN11 expression as a predictive biomarker for PARPi or platinum agents.
Abstract 12335: Acacetin, a Potent Transient Outward Current Blocker, May Serve as a Novel Therapeutic for KCND3-encoded Kv4.3 Gain-of-function-associated Brugada Syndrome
Authors: Dan Ye, Wei Zhou, David J Tester, Hector Barajas-Martinez, Dan Hu, Charles N Antzelevitch, Michael J Ackerman
Journal: Circulation (2019)

Introduction: The transient outward current (Ito) that mediates early (phase 1) repolarization is conducted by the KCND3-encoded Kv4.3 pore-forming α-subunit. KCND3 gain-of-function mutations have ...
Early Cardiac Toxicity Associated With Post-Transplant Cyclophosphamide in Allogeneic Stem Cell Transplantation
Authors: Rémy Duléry, Razan Mohty, Myriam Labopin, Simona Sestili, Florent Malard, Eolia Brissot, Giorgia Battipaglia, Clémence Médiavilla, Anne Banet, Zoé Van de Wyngaert, Annalisa Paviglianiti, Ramdane Belhocine, Françoise Isnard, Simona Lapusan, Rosa Adaeva, Anne Vekhoff, Tounes Ledraa, Ollivier Legrand, Ariel Cohen, Agnès Bonnin, Stéphane Ederhy, Mohamad Mohty
Journal: JACC CardioOncology (2021)

Post-transplant cyclophosphamide (PT-Cy) has become a standard of care in haploidentical hematopoietic stem cell transplantation (HSCT) to reduce the risk of graft-versus-host disease. However, data on cardiac events associated with PT-Cy are scarce.This study sought to assess the incidence and clinical features of cardiac events associated with PT-Cy.The study compared clinical outcomes between patients who received PT-Cy (n = 136) and patients who did not (n = 195), with a focus on early cardiac events (ECE) occurring within the first 100 days after HSCT. All patients had the same systematic cardiac monitoring.The cumulative incidence of ECE was 19% in the PT-Cy group and 6% in the no-PT-Cy group (p < 0.001). The main ECE occurring after PT-Cy were left ventricular systolic dysfunction (13%), acute pulmonary edema (7%), pericarditis (4%), arrhythmia (3%), and acute coronary syndrome (2%). Cardiovascular risk factors were not associated with ECE. In multivariable analysis, the use of PT-Cy was associated with ECE (hazard ratio: 2.7; 95% confidence interval: 1.4 to 4.9; p = 0.002]. Older age, sequential conditioning regimen, and Cy exposure before HSCT were also associated with a higher incidence of ECE. Finally, a history of cardiac events before HSCT and ECE had a detrimental impact on overall survival.PT-Cy is associated with a higher incidence of ECE occurring within the first 100 days after HSCT. Patients who have a cardiac event after HSCT have lower overall survival. These results may help to improve the selection of patients who are eligible to undergo HSCT with PT-Cy, especially older adult patients and patients with previous exposure to Cy.
A phase 1 multicenter, dose expansion study of ARX788 as monotherapy in patients with HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma (ACE-Gastric-01).
Authors: Yang Zhang, Miaozhen Qiu, Jufeng Wang, Yanqiao Zhang, Xianglin Yuan, Tao Zhang, Jinchun Yan, Gaozhun Xiong, Yanping Ji, Xuejun Liang, Gang Xia, Rui-hua Xu
Journal: Journal of Clinical Oncology (2021)

e16059 Background: ARX788 is a novel antibody drug conjugate (ADC) that consists of human epidermal growth factor receptor 2 (HER2) targeted monoclonal antibody (mAb) linked to a cytotoxic payload, AS269, a highly potent tubulin inhibitor. In a phase 1 study of ARX788 in HER2-positive advanced breast cancer (CTR20171162/ACE-Breast-01), the objective response rate (ORR) was 74 % (14/19) at 1.5 mg/kg Q3W. Here we present the safety, tolerability, and antitumor activity of ARX788 in HER2-positive advanced gastric and gastroesophageal junction (GEJ) cancer in the phase 1 (ACE-Gastric-01) study. Methods: participants with HER2+ gastric/GEJ cancer were administrated with ARX788 intravenously at dose levels of 1.3, 1.5, and 1.7 mg/kg Q3W to determine the maximum tolerated dose and recommended phase 2 dose; and to evaluate the antitumor activity. Efficacy endpoints included objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1. Results: As of Jan 29, 2021, a total of 23 participants including 9 at the 1.3 mg/kg and 14 at the 1.5 mg/kg received at least one dose of ARX788. All patients were heavily treated previously. The confirmed ORR was 42.9% and 46.2% at the 1.3 and 1.5 mg/kg, respectively. As of the cut-off date, six participants were still under treatment with two of them were treated for longer than 12 months. Most AEs were grade 1 or 2 and were manageable. There were 2 drug-related grade 3 AEs and no grade 4 or 5 AEs occurred. No DLT was observed and the MTD was not reached. The dose expansion at the 1.7 mg/kg Q3W cohort is still ongoing and the mature data will be presented later. Conclusions: ARX788 was well tolerated with promising antitumor activity in patients with HER2-positive advanced gastric and GEJ adenocarcinoma. Clinical trial information: CTR20190639. [Table: see text]
冠動脈疾患の疑いのある患者におけるストレス時Tl-201心筋画像陰性にもかかわらずI-123BMIPP陽性であることの診断的意義
Authors: Hatano Tsuguhisa, Chikamori Taishiro, Usui Yasuhiro, Morishima Takayuki, Hida Satoshi, Yamashina Akira
Journal: Circulation (2006)
Cancer care system strengthening (Pendharkar model) offers uninterrupted care continuum during COVID19 pandemic.
Authors: Dinesh Pendharkar, Chandramauli Tripathi
Journal: Journal of Clinical Oncology (2021)

e13540 Background: District cancer care programme is operational in more than 150 districts of India. This programme has created nodal cancer units n government run district general hospitals offering cancer related services including chemotherapy and palliative care. During pandemic (COVID19), due lockdown, cancer patients were not able to access tertiary level specialised cancer centres. Aim of this presentation is to reaffirm the necessity of health system strengthening at peripheral level. Methods: With the aim of decentralization and task shifting, district cancer care programme is being implemented in 8 states of India. One general duty medical officers and paramedical staff is trained to assist cancer patients. The physician work under 24 x7 mentorship of oncology team. The government has created a physical cancer care unit with availability of some essential chemotherapy drugs as well. Cancer patients can access these units for assistance in diagnostics, follow-up, toxicity care, chemotherapy and palliative care. Results: We analysed data from few districts in year 2020. The number of patients vesting the units showed an increase during months of total lockdown. Data from 14 districts were analysed. It shows that number of outpatient visits and chemotherapy sessions were higher during strict lockdown. From January 2020 to December 2020 there were 19,273 outpatient visits, and 9,788 inpatient visits. During months of a strict lockdown-March, April, May, June the number increased.7,729 sessions of chemotherapy were performed and more than 2,230 new cases were registered during this year. Conclusions: The pandemic has brought new challenges and has compelled us to learn ways of care continuum. The most important has been the necessity of decentralisation of specialised care, its evenly and equitable distribution. District cancer care programme, as a measure of health system strengthening, which is being evolved in India has further emphasized the importance of such a system building.
Novel antibody cocktail targeting Bet v 1 rapidly and sustainably treats birch allergy symptoms in a phase 1 study
Authors: Philippe Gevaert, Jarno De Craemer, Natalie De Ruyck, Sylvie Rottey, Jan de Hoon, Peter W. Hellings, Bram Volckaert, Kristof Lesneuck, Jamie M. Orengo, Amanda Atanasio, Mohamed A. Kamal, Hisham Abdallah, Vishal Kamat, Robert Dingman, Michelle DeVeaux, Divya Ramesh, Lorah Perlee, Claire Q. Wang, David M. Weinreich, Gary Herman, George D. Yancopoulos, Meagan P. O’Brien
Journal: Journal of Allergy and Clinical Immunology (2021)

The efficacy of an allergen-specific IgG cocktail to treat cat allergy suggests that allergen-specific IgG may be a major protective mechanism elicited by allergen immunotherapy.Extending these findings, we tested a Bet v 1-specific antibody cocktail in birch-allergic subjects.This was a phase 1, randomized, double-blind, study with 2 parts. Part A administered ascending doses of the Bet v 1-specific antibody cocktail REGN5713/14/15 (150-900 mg) in 32 healthy adults. Part B administered a single subcutaneous 900-mg dose or placebo in 64 birch-allergic subjects. Total nasal symptom score response to titrated birch extract nasal allergen challenge and skin prick test (SPT) with birch and alder allergen were assessed at screening and days 8, 29, 57, and 113 (SPT only); basophil activation tests (n = 26) were conducted.Single-dose REGN5713/14/15 significantly reduced total nasal symptom score following birch nasal allergen challenge relative to baseline. Differences in total nasal symptom score areas under the curve (0-1 hour) for subjects treated with REGN5713/14/15 versus those given placebo (day 8: -1.17, P = .001; day 29: -1.18, P = .001; day 57: -0.85, P = .024) and titration SPT with birch difference in area under the curve of mean wheal diameters for subjects treated with REGN5713/14/15 versus placebo (all P < .001) were sustained for ≥2 months; similar results were observed with alder SPT. REGN5713/14/15 was well tolerated. Basophil responsiveness to birch-related allergens was significantly decreased in subjects treated with REGN5713/14/15 versus those given placebo on days 8, 57, and 113 (all P < .01).Single-dose REGN5713/14/15 was well tolerated and provided a rapid (1 week) and durable (2 months) reduction in allergic symptoms after birch allergen nasal allergen challenge, potentially offering a new paradigm for the treatment of birch allergy symptoms.
<i>Curvularia alcornii</i> Infection
Authors: Adam R. Williams, Shanti Narayanasamy
Journal: New England Journal of Medicine (2021)

A 53-year-old man presented with fever and sudden onset of lower-leg paralysis. Imaging revealed a 9-cm ascending aortic pseudoaneurysm and multiple arterial emboli. Cultures of intraoperative tissue grew the dematiaceous mold C. alcornii.
Safety and Efficacy of Deferred Autologous Stem Cell Transplantation in Patients with Systemic AL Amyloidosis with Significant Cardiac Involvement at Presentation
Authors: Richa Manwani, Ute Hegenbart, Darren Foard, Shameem Mahmood, Sajitha Sachchithanantham, Kwee Yong, Rakesh Popat, Charalampia Kyriakou, Neil Rabin, Marianna Fontana, Carol Whelan, Helen Lachmann, Thirusha Lane, Candida Quarta, Julian Gillmore, Tobias Dittrich, Christoph Kimmich, Philip Hawkins, Stefan Schönland, Ashutosh D. Wechalekar
Journal: Blood (2017)
Depressive symptoms, mental wellbeing, and substance use among adolescents before and during the COVID-19 pandemic in Iceland: a longitudinal, population-based study
Authors: Ingibjorg Eva Thorisdottir, Bryndis Bjork Asgeirsdottir, Alfgeir Logi Kristjansson, Heiddis Bjork Valdimarsdottir, Erla Maria Jonsdottir Tolgyes, Jon Sigfusson, John Philip Allegrante, Inga Dora Sigfusdottir, Thorhildur Halldorsdottir
Journal: The Lancet Psychiatry (2021)
Cost-effectiveness of atezolizumab and bevacizumab in advanced hepatocellular carcinoma.
Authors: Kishan Patel, Stacey Stein, Janki Luther, Scott F. Huntington
Journal: Journal of Clinical Oncology (2021)

e18829 Background: The IMbrave150 trial found that atezolizumab and bevacizumab significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with locally advanced metastatic or unresectable hepatocellular carcinoma (HCC), compared to sorafenib. However, atezolizumab and bevacizumab are costly treatments and are administered indefinitely until disease progression. Therefore, it is unclear whether atezolizumab-bevacizumab is cost-effective in this clinical setting. Methods: We constructed a partitioned survival model to compare the costs and effectiveness of atezolizumab-bevacizumab to sorafenib in advanced HCC. PFS and OS curves for each treatment strategy were derived from the IMbrave150 trial using parametric survival modeling. The utility of each health state and the costs of treatment, adverse events, and terminal care were derived from literature and Medicare fee schedules. We calculated the incremental cost-effectiveness ratio (ICER) of atezolizumab-bevacizumab from a US healthcare perspective, using a lifetime horizon, an annual discount rate of 3%, and a willingness-to-pay threshold of $150,000/quality-adjusted life year (QALY). One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of model conclusions. Results: Atezolizumab-bevacizumab was associated with an incremental cost of $102,648 and an incremental effectiveness of 0.42 QALYs compared to sorafenib, leading to an ICER of $244,213/QALY (Table). The price of atezolizumab would need to be reduced by 40% (from ̃$9,400 to ̃$5,700 per dose) or the price of bevacizumab would need to be reduced by 47% (from ̃$8,400 to ̃$4,400 per dose) for atezolizumab-bevacizumab to be cost-effective compared to sorafenib. Alternatively, the price of both atezolizumab and bevacizumab would need to be simultaneously decreased by ̃21% for the combination therapy to be cost-effective. Our model was most sensitive to the hazard ratios (HR) of OS and PFS; varying the HRs across the 95% confidence interval reported in IMbrave150 (0.42-0.79) corresponded to ICERs of $137,435/QALY and $621,365/QALY, respectively. During probabilistic sensitivity analyses, &gt;99%, 99%, and 90% of iterations produced ICERs greater than willingness-to-pay thresholds of $50,000/QALY, $100,000/QALY, and $150,000/QALY, respectively. Conclusions: Use of atezolizumab-bevacizumab for advanced HCC is unlikely to be cost-effective under current pricing. Significant price reduction of atezolizumab and/or bevacizumab would be required to reduce the ICER to a more widely acceptable value.[Table: see text]
Mechanical Complications of Acute Myocardial Infarction: A Scientific Statement From the American Heart Association
Authors: Abdulla A. Damluji, Sean van Diepen, Jason N. Katz, Venu Menon, Jacqueline E. Tamis-Holland, Marie Bakitas, Mauricio G. Cohen, Leora B. Balsam, Joanna Chikwe
Journal: Circulation (2021)

Over the past few decades, advances in pharmacological, catheter-based, and surgical reperfusion have improved outcomes for patients with acute myocardial infarctions. However, patients with large infarcts or those who do not receive timely revascularization remain at risk for mechanical complications of acute myocardial infarction. The most commonly encountered mechanical complications are acute mitral regurgitation secondary to papillary muscle rupture, ventricular septal defect, pseudoaneurysm, and free wall rupture; each complication is associated with a significant risk of morbidity, mortality, and hospital resource utilization. The care for patients with mechanical complications is complex and requires a multidisciplinary collaboration for prompt recognition, diagnosis, hemodynamic stabilization, and decision support to assist patients and families in the selection of definitive therapies or palliation. However, because of the relatively small number of high-quality studies that exist to guide clinical practice, there is significant variability in care that mainly depends on local expertise and available resources.
Mutational landscape of Chinese osteosarcoma patients.
Authors: Shuier Zheng, Chenliang Zhou, Guowei Qian, Yan Zhou, Zan Shen, Yan Yin, Tianhao Mu, Tanxiao Huang
Journal: Journal of Clinical Oncology (2021)

e23512 Background: Osteosarcoma is the bone tumor which is still incompletely understood. This disease most commonly affects children, adolescents, and young adults. The next-generation sequencing technology is a powerful tool to investigate the genetic basis for this disease. Methods: 12 Chinese patients diagnosed with osteosarcoma were enrolled in this study. The tumor tissue or serial blood sample was collected for each individual and the next-generation sequencing was performed using Haplox 605-gene panel. Mutational landscape was analyzed in the cohort. To explore the biological function of the most frequently mutated genes, GO term and KEGG pathway enrichment analysis were performed. Results: In total, 54 genes related to cancer were detected mutated in these patients. The most frequent alterations were CNKN2A(5/12), CSMD3(3/12), FGFR1(3/12), FGFR3(3/12), FGF4(3/12), TP53(3/12), KRAS(3/12), JAK2(3/12). While CNKN2A works as the stabilizer of the tumor suppressor protein TP53, we found 5 patients were with CNKN2A deletion. Also, there were 3 patients with FGFR1 amplification, 3 patients with TP53 substitution, 3 patients with FGFR3 deletion, and 3 patients with CSMD3 substitution. For FGF4, there were 2 deletions and 1 substitution. For KRAS, there were 2 amplifications and 1 substitution. For JAK2, there were 2 deletions and 1 substitution. The enrichment analysis revealed that positive regulation of biological process, developmental process, and signaling were the most enriched (p &lt; 10 -6 ). Conclusions: Our study explored the most frequently mutated gene in Chinese osteosarcoma patients. Moreover, the enrichment analysis indicated that the genes were enriched in positive regulation of biological process, developmental process, and signaling.
The effect of ethanol on the habit and in vitro aerodynamic results of dry powder inhalation formulations containing ciprofloxacin hydrochloride
Authors: Edit Benke, Christina Winter, Piroska Szabó-Révész, Eva Roblegg, Rita Ambrus
Journal: Asian Journal of Pharmaceutical Sciences (2021)

In the case of dry powder inhalation systems (DPIs), the development of carrier-free formulations has gained increased attention. Thereby, spray-drying is a promising technology and is widely used to produce carrier-free DPIs. Numerous works have been published about the co-spray-drying of active ingredients with various solid excipients and their effect on the physicochemical characteristics and aerodynamic properties of the formulations. However, only a few studies have been reported about the role of the solvents used in the stock solutions of spray-dried formulations. In the present work, DPI microcomposites containing ciprofloxacin hydrochloride were prepared by spray-drying in the presence of different ethanol concentrations. The work expresses the roughness, depth and width of the dimples for particle size as a novel calculation possibility, and as a correlation between the MMAD/D0.5 ratio and correlating it with cohesion work, these new terms and correlations have not been published - to the best of our knowledge - which has resulted in gap-filling findings. As a result, different proportions of solvent mixtures could be interpreted and placed in a new perspective, in which the influence of different concentrations of ethanol on the habit of the DPI formulations, and thus on in vitro aerodynamic results. Based on these, it became clear why we obtained the best in vitro aerodynamic results for DPI formulation containing 30% ethanol in the stock solution.