tbuckley/cabot-search huggingface dataset:
Oct4 promotes M2 macrophage polarization through upregulation of macrophage colony-stimulating factor in lung cancer
Authors: Chia-Sing Lu, Ai-Li Shiau, Bing-Hua Su, Tsui-Shan Hsu, Chung-Teng Wang, Yu-Chu Su, Ming-Shian Tsai, Yin-Hsun Feng, Yau-Lin Tseng, Yi-Ting Yen, Chao-Liang Wu, Gia-Shing Shieh
Journal: Journal of Hematology & Oncology (2020)

Abstract Background Expression of Oct4 maintains cancer stem cell (CSC)-like properties in lung cancer cells and is correlated with poor prognosis of lung adenocarcinoma. M2-type tumor-associated macrophages (TAMs) promote cancer cell migration and metastasis. Tumor microenvironments promote monocyte differentiation into M2 TAMs via a complex cytokine-based connection. We explored the role of Oct4 in cytokine secretion in lung cancer and its impact on M2 TAM polarization. Methods Monocytes co-cultured with the conditioned medium from Oct4-overexpressing lung cancer cells were used to investigate M2 TAM differentiation. The inflammatory factors in the conditioned medium of Oct4-overexpressing A549 cells were examined using human inflammation antibody arrays. The correlations of Oct4, macrophage colony-stimulating factor (M-CSF), and M2 TAMs were validated in lung cancer cells, syngeneic mouse lung tumor models, and clinical samples of non-small cell lung cancer (NSCLC). Results Oct4-overexpressing A549 cells expressed elevated levels of M-CSF, which contributed to increased M2 macrophages and enhanced tumor migration. Overexpression of Oct4 enhanced tumor growth and reduced the survival of lung tumor-bearing mice, which was correlated with increased number of M2 macrophages in lung cancer. Notably, NSCLC patients with high expression levels of Oct4, M-CSF, and M2 TAMs had the poorest recurrence-free survival. A positive correlation between Oct4, M-CSF, and M2 TAMs was observed in the tumor tissue of NSCLC patient. Treatment with all-trans retinoic acid exerted anti-tumor effects and reduced M2 TAMs in tumor-bearing mice. Conclusions Our results indicate that Oct4 expressed by lung cancer cells promotes M2 macrophage polarization through upregulation of M-CSF secretion, leading to cancer growth and metastasis. Our findings also implicate that the Oct4/M-CSF axis in M2 macrophage polarization may be potential therapeutic targets for lung cancer.
A phase II study of MT-3724, a novel CD20-targeting engineered toxin body, to evaluate safety, pharmacodynamics, and efficacy in subjects with relapsed or refractory diffuse large B-cell lymphoma.
Authors: Adolfo Enrique Diaz Duque, Tetiana Perekhrestenko, Vasile Musteata, Mamia Zodelava, Troy H. Guthrie, Thomas Strack, Christine Burnett, Sarah Wilson, Roger J. Waltzman, Tara D. Baetz, Daniel O. Persky
Journal: Journal of Clinical Oncology (2020)

TPS8074 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-3724 represents a novel ETB modality comprised of an anti-CD20 single-chain variable fragment genetically fused to SLT-A. It is capable of efficient internalization once bound to CD20 and can induce potent direct cell-kill via enzymatic ribosome inactivation. MT-3724 is currently being studied in three ongoing Phase 2 studies for relapsed or refractory diffuse large B-cell lymphoma (r/rDLBCL). Methods: The primary objective of this single-arm, Phase 2 study (NCT02361346) is to determine the efficacy of MT-3724 monotherapy in r/rDLBCL based on overall response rate (ORR), defined as the proportion of subjects with a complete/partial response according to the Lugano criteria, as assessed by independent, central review. Key secondary objectives include safety, progression-free survival, investigator‐assessed ORR, duration of response, overall survival, and pharmacodynamics. Adverse events will be assessed and documented according to Common Terminology Criteria for Adverse Events version 5.0. Key eligibility criteria include adult subjects with histologically confirmed, r/rDLBCL, with ≥2 prior standard of care systemic NHL treatment regimens, and ≥1 measurable lesion. As rituximab and other CD20-targeting antibodies compete with MT-3724 for the same CD20 domain, minimum washout periods from these agents must be observed. Subjects remain eligible post stem cell transplant or chimeric antigen receptor T-cell therapy. Subjects will receive 50 µg/kg MT-3724 IV over 1 hour on Days 1, 3, 5, 8, 10 and 12 of a 21-day treatment cycle. The anticipated sample size is N = 100. Interim analyses will be performed to confirm minimum efficacy thresholds based on the encouraging data observed in the completed phase 1 portion of the study [Hamlin et al. Blood 2019;134(Suppl 1):4098]. Multiple global sites are enrolling subjects. Clinical trial information: NCT02361346 .
Multicentre randomized phase II trial of olaparib as maintenance therapy in platinum-sensitive advanced endometrial carcinoma: The GINECO-UTOLA study.
Authors: Florence Joly, Pierre Emmanuel Brachet, Sophie Abadie Lacourtoisie, Bernard Asselain, Anne Floquet, Olivier Collard, Manuel Rodrigues, Karen Leroy, Corinne Jeanne, Alexandra Leary, Sarah Betrian, Benoit You, Yolanda Fernandez Diez, Anne-Claire Hardy-Bessard, Annick Chevalier, Elsa Kalbacher, Corina Cornila, Cyril Foa, Philippe Follana, Jerome Alexandre
Journal: Journal of Clinical Oncology (2020)

TPS6109 Background: Advanced endometrial cancer (EC) patients relapse despite treatment with combination chemotherapy and have a short progression-free survival (PFS). Data from the TGCA suggest opportunities to targeting DNA repair in women with EC. Particularly type 4 (High copy number or serous like, with frequent TP53 mutations) and type 2 (microsatellite instability hypermutated) EC can be associated with defects in double strand break DNA repair by homologous recombination (HR) and could potentially be targeted by olaparib. We propose a placebo-controlled, multicenter, two-arm, phase II trial comparing olaparib versus placebo in maintenance therapy after chemotherapy in patients with advanced/metastatic EC. Methods: The primary objective of this trial is to evaluate the efficacy of maintenance olaparib in comparison to placebo after platinum based chemotherapy, defined by PFS according to Recist. Key eligibility criteria include: advanced/metastatic histologically confirmed EC (excepted carcino-sarcoma, small cells&amp; neuroendocrine); prior surgery, adjuvant chemotherapy, radiation and hormonal therapy are permitted; objective or stable response after first-line chemotherapy is mandatory. 147 patients are randomized (2:1) after chemotherapy to receive Olaparib 300mg twice daily or placebo in maintenance after at least 4 cycles of platinum based chemotherapy. Olaparib/placebo is continued until disease progression, unacceptable toxicity, or withdrawal. Stratification is on IHC P53 and MMR status. Primary hypothesis is a 66.7% relative increase in the median PFS rate in the olaparib arm (from 4.5 to 7.5 months), corresponding to a 0.60 Hazard Ratio. Secondary endpoints include PFS according to P53, MMR and NGS HRD status, PFS2, disease specific survival, time to subsequent therapy, overall survival, objective response, disease control rate, patient reported outcomes (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24, EORTC-FA, EQ5D) and safety. Trial is recruiting in France (in February n= 40 randomization). Conclusion: this will be the first study that evaluate the efficacy of olaparib in maintenace after chemotherapy in advanced/metastastic EC, stratified on molecular profil. Clinical trial information: NCT03745950.
A Big Ten Cancer Research Consortium phase II trial of pembrolizumab with carboplatin and paclitaxel for advanced or recurrent endometrial cancer.
Authors: Mario Javier Pineda, Jeanne Schilder, Emily K. Hill, Deanna Gek Koon Teoh, Emma Longley Barber, Sharon E. Robertson, Anna Everett Strohl, Jiahui Xu, Masha Kocherginsky, Daniela Matei
Journal: Journal of Clinical Oncology (2020)

6022 Background: There are limited chemotherapeutic options for patients (pts) with advanced or recurrent endometrial cancer (EC). Reported objective response rates (ORR) for first-line doxorubicin/cisplatin/ paclitaxel combination therapy was 57%; with a median progression-free survival (PFS) of 8.3 months. The goal of this phase II study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in pts with measurable advanced or recurrent EC. Methods: This was a single-arm, open-label, multi-center phase II study for pts with RECIST measurable advanced or recurrent EC coordinated by the Big Ten Cancer Research Consortium. Patients may have had received 1 prior platinum-based regimen, with a platinum free interval &gt; 6 months, &lt; one non-platinum chemotherapy, or prior hormonal therapy. Pts received carboplatin AUC 6, paclitaxel 175mg/m 2 (CT) and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles; with dose reduced for prior radiation. The primary endpoint was ORR per immune-related RECIST. Planned sample size of 46 subjects provided 77% power to detect 15% ORR improvement compared to historical controls, with one-tailed test and 10% type I error rate. Results: 46 pts were enrolled. Median age was 67 (range: 43-86). 32 pts had recurrent and 14 had primary metastatic EC. Histological types were: 26 endometrioid, 11 serous, 3 clear cell, 6 other. 19 patients had received prior carboplatin/paclitaxel, 23 pelvic EBRT, 14 brachytherapy, 1 adriamycin and 1 hormonal therapy. Grade 3-4 adverse events (AEs) included: laboratory abnormalities (20), hematological (8), metabolism (6), nervous system (4), gastrointestinal (2), and others (6). There were 15 grade 3-4 SAEs occurring in 7 pts: vomiting (1), anaphylaxis (3), fever (2), dehydration (1), syncope (2), vascular (2), fatigue (1), neurological (2), thrombocytopenia (1), and no grade 5 SAEs. 36 patients were evaluable for response at the time of abstract submission. ORR was 77.8% (28/36) and median PFS was 10.55 months. Conclusions: The addition of pembrolizumab to standard of care CT chemotherapy for advanced or recurrent EC induced a clinically significant improvement in ORR compared to historical outcomes and toxicity did not exceed anticipated toxicity with standard treatment, supporting further testing in a phase III trial. Clinical trial information: NCT02549209.
Covid-19: Johnson is on back foot over next steps to control pandemic
Authors: Adrian O’Dowd
Journal: BMJ (2020)

The government’s next steps in handling the covid-19 pandemic have come under growing scrutiny with increasingly critical observations from MPs in a recent parliamentary quizzing of the prime minister.

Boris Johnson spent around 100 minutes answering questions from many MPs during a 27 May evidence session of the House of Commons liaison committee, comprising the chairs of all select committees. A fiery evidence session on the science, impact, and way forward regarding the coronavirus was dominated by questions about the recent controversy over the government adviser Dominic Cummings and whether his actions had broken lockdown rules.1

Almost a third of the session was spent with the prime minister repeating his support for Cummings and rejecting a call for an official inquiry into whether the adviser had broken any rules, to which he replied, “Quite frankly, I’m not certain right now, that an inquiry into that matter is a very good use of official time.”

Other issues were discussed, such as why the …
基层医院急诊治疗180例自杀患者临床分析
Authors: 董衍军
Journal: BMJ (2006)

由于种种原因,自杀的发生率呈上升趋势,农村人口自杀也是一个不容忽视的问题.了解自杀的现状及临床特征并制定有效的防范措施极为重要.2003年1月至2005年我院急诊收治患者共14 154例,其中自杀者180例,占1.27%.现对此180例患者的临床资料进行分析。
The role of adjuvant chemotherapy in the management of surgically resected primary pulmonary salivary gland-type carcinomas.
Authors: Moustafa Younis, Sunpreet Rakhra, Kevin F Kennedy, Jessica K Heimes, John Russell Davis, Lara Kujtan, Janakiraman Subramanian
Journal: Journal of Clinical Oncology (2020)

e21009 Background: Primary pulmonary salivary gland-type carcinomas (PSGC) are rare tumors. There are limited data on the role of adjuvant chemotherapy after surgical resection of these tumors. Here, we examine the role of adjuvant chemotherapy in the management of resected PSGC. Methods: The National Cancer Database was queried to identify patients with PSGC who underwent surgical resection. Histology codes 8200- adenoid cystic carcinoma (ACC), 8430- mucoepidermoid carcinoma (MEC), 8550- acinic cell carcinoma (AIC) and 8551- adenocarcinoma, acinar predominant were used. Patients were divided based on chemotherapy status. Summary and univariate analysis was performed. Multivariable proportional hazard regression analyses were used to obtain hazard ratios (HR). Results: A total of 6685 patients, with a mean (±SD) age of 66.1 ± 11.0 years, were included; 4148 (62%) were females. Most patients were Caucasian (84%). Chemotherapy was administered in 1141 patients (17%); multiagent chemotherapy: n = 1034 (91%). AIC was the most common subtype (n = 6302, 94%) followed by MEC (n = 304, 4.6%) and ACC (n = 73, 1.1%). Patients who received chemotherapy were younger (64.0 ± 9.0 vs 66.5 ± 11.3; p &lt; 0.001), otherwise, there was no significant difference in baseline demographics. Unadjusted 5-year survival for stage I PSGC was significantly lower in the chemotherapy arm (60.5% vs 72%, p &lt; 0.001). Chemotherapy did not improve survival in resected stage II or III PSGC. Overall survival was inferior with chemotherapy on multivariable analysis (adjusted HR: 1.32, 95%CI (1.13-1.55), p = 0.0006). Older age, male gender, positive margins, higher clinical stage, comorbidities, rural population and pneumonectomy were associated with lower overall survival (Table). Conclusions: Contrary to previous studies AIC is the most common tumor type among PSGC. Adjuvant chemotherapy is associated with worse survival in resected PSGC and current guidelines for administering adjuvant chemotherapy in resected lung cancer is inadequate for this population. [Table: see text]
Tumor ablation plus co-administration of CpG and saponin adjuvants affects IL-1 production and multifunctional T cell numbers in tumor draining lymph nodes
Authors: Tonke K Raaijmakers, Renske J E van den Bijgaart, Martijn H den Brok, Melissa Wassink, Annemarie de Graaf, Jori A Wagenaars, Stefan Nierkens, Marleen Ansems, Gert Jan Scheffer, Gosse J Adema
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Tumor ablation techniques, like cryoablation, are successfully used in the clinic to treat tumors. The tumor debris remaining in situ after ablation is a major antigen depot, including neoantigens, which are presented by dendritic cells (DCs) in the draining lymph nodes to induce tumor-specific CD8 + T cells. We have previously shown that co-administration of adjuvants is essential to evoke strong in vivo antitumor immunity and the induction of long-term memory. However, which adjuvants most effectively combine with in situ tumor ablation remains unclear. Methods and results Here, we show that simultaneous administration of cytidyl guanosyl (CpG) with saponin-based adjuvants following cryoablation affects multifunctional T-cell numbers and interleukin (IL)-1 induced polymorphonuclear neutrophil recruitment in the tumor draining lymph nodes, relative to either adjuvant alone. The combination of CpG and saponin-based adjuvants induces potent DC maturation (mainly CpG-mediated), antigen cross-presentation (mainly saponin-based adjuvant mediated), while excretion of IL-1β by DCs in vitro depends on the presence of both adjuvants. Most strikingly, CpG/saponin-based adjuvant exposed DCs potentiate antigen-specific T-cell proliferation resulting in multipotent T cells with increased capacity to produce interferon (IFN)γ, IL-2 and tumor necrosis factor-α in vitro. Also in vivo the CpG/saponin-based adjuvant combination plus cryoablation increased the numbers of tumor-specific CD8 + T cells showing enhanced IFNγ production as compared with single adjuvant treatments. Conclusions Collectively, these data indicate that co-injection of CpG with saponin-based adjuvants after cryoablation induces an increased amount of tumor-specific multifunctional T cells. The combination of saponin-based adjuvants with toll-like receptor 9 adjuvant CpG in a cryoablative setting therefore represents a promising in situ vaccination strategy.
Fluconazole vs. voriconazole prophylaxis for prevention of invasive fungal infections post haploidentical stem cell transplant.
Authors: Issam Hamadeh, Zainab Shahid, Saurabh Chhabra, Anjeanette Mendez, Jiaxian He, Candace Butler, Brandy Dodd
Journal: Journal of Clinical Oncology (2020)

e19504 Background: IFIs are one of the most detrimental complications of profound and prolonged neutropenia post-allogeneic SCT. Prophylaxis with broad spectrum azole antifungals has become standard of care given favorable outcomes associated with their use in this setting. Nonetheless, the choice of antifungal agent varies between institutions due to absence of consensus guidelines in patients undergoing haploidentical SCT. Methods: Non-interventional retrospective study seeking to compare efficacy of fluconazole vs. voriconazole for prevention of IFI post haploidentical SCT for hematologic malignancies. SCT databases at two academic insitutions (one uses fluconazole and other uses voriconazole) were queried to identify patients who underwent allogeneic SCT from April 2012 until March 2018, and received prophlaxis with either voriconazole (group I) or fluconazole (group II). Patients with intent to start prophylaxis with fluconazole or voriconazole were included, even if antifungal agent was changed later. Primary endpoint was cumulative incidence of breakthrough IFIs (based on MSG criteria) on day +100 and +180. Fisher exact test was used to compare rates of breakthrough IFIs between two cohorts. Secondary endpoint was overal survival (OS). Kaplan Meiers analysis was performed to compare OS on day +180 and 1-year post SCT. Results: The cohort included 141 patients (group I: 75 and group II: 66). Percentage of patients who underwent transplant for leukemia was higher in group I compared to group II (77.3% vs. 56.1%, p &lt; 0.001). A haploidentical SCT was performed in 62.7% of patients in group I compared to 100% in group II (p &lt; 0.001). All patients received non-myeloablative conditioning. There was no statistically significant difference in rates of IFIs between two groups on day +100 (0% in I vs. 4.5% in II, p = 0.9) and +180 (1.4% vs. 4.6%, p = 0.2). A significant difference in OS was noted on day +180 and at 1-year in univariate analysis (Table). Conclusions: Our findings suggest that prophylactic use of either voriconazole or fluconazole after haploidentical SCT is associated with low rates of IFIs. However, survival data favored voriconazole over fluconazole. [Table: see text]
Diagnostic value of susceptibility-weighted imaging for intracranial cavernous hemangioma
Authors: Lin Ma, Jin-you Liu, Guang-shan Tang, Yue-jian Yang
Journal: BMJ (2012)

To explore the diagnostic value of susceptibility weighted imaging (SWI) for intracranial cavernous hemangioma.The magnetic resonance sequences of SWI,conventional imaging (MRI) and diffusion-weighted imaging (DWI) were performed in 37 patients of intracranial cavernous hemangioma to compare their different imaging capacities.Among them,the number of lesions found on T1WI,T2WI,DWI and SWI sequences were 40,41,42 and 50 respectively.Thus SWI may detect regular MRI negative or smaller lesions of intracranial cavernous hemangioma.

Key words: 
Magnetic resonance imaging ;  Hemangioma, cavernous, central, nervous system
Concurrent nivolumab and ipilimumab with brain stereotactic radiosurgery for brain metastases from non-small cell lung cancer: A phase I trial.
Authors: Jing Li, Yan Wang, Chad Tang, James William Welsh, Nandita Guha- Thakurta, Brett W. Carter, Jeffrey Scott Wefel, Amol J. Ghia, Debra Yeboa, Mary Frances McAleer, Caroline Chung, Kristina D Woodhouse, Yasir Elamin, Xiuning Le, Tina Cascone, Marcelo Vailati Negrao, Ferdinandos Skoulidis, Renata Ferrarotto, John Heymach, Mehmet Altan
Journal: Journal of Clinical Oncology (2020)

2531 Background: Nivolumab (nivo) and ipilimumab (ipi) were found in the recent phase III CheckMate 227 trial to have an overall survival benefit over chemotherapy for advanced non-small cell lung cancer (NSCLC). However, patients (pts) with untreated brain metastasis (mets) were excluded from that trial. Because 30% of NSCLC pts develop brain mets, we tested nivo/ipi with concurrent stereotactic radiosurgery (SRS) for NSCLC pts with active brain mets. Methods: We report the safety data from the phase I portion of an ongoing phase I/II single-institution trial in which one treatment group was given SRS with nivo (3 mg/kg) every 2 weeks (wks) plus ipi (1 mg/kg) every 6 wks x 4 cycles, followed by maintenance nivo (480 mg) every 4 wks until disease progression, unacceptable toxicity, or withdrawal of consent. Brain SRS was delivered within 7 days of initiation of nivo/ipi. The primary endpoints were safety and 4-month (mo) intracranial progression-free survival (PFS). Dose-limiting toxicity (DLT) was defined as &gt; 15% intracranial toxicity (&gt;G3 hypophysitis / neurologic toxicity) or &gt; 30% extracranial toxicity (&gt;G3 non-dermatologic non-lab toxicity or &gt;G4 dermatologic / lab toxicity), refractory to medical management, assessed at 8 wks after treatment initiation. Target accrual for phase I was 10 evaluable pts, with enrollment suspended after every 5 pts for DLT assessment. Results: Since June 15, 2018, 13 pts were enrolled and 10 were evaluable for DLT. The median follow-up time was 6.8 mo (range 1.2‒18). As of January 6, 2020, only 1 pt had DLT-defined toxicity and thus the predefined stopping criteria were not met. This pt had G3 seizure right after SRS that resolved within a week, and then had increased but asymptomatic CNS edema 4 wks later. Aside from DLTs, 3 pts (25%) developed treatment-related G3 (elevated liver function tests, fatigue, nausea, adrenal insufficiency, and myocarditis) or G4 events (pneumonitis/acute respiratory distress syndrome in 1 pt with confirmed influenza at 7 mos after treatment initiation). This pt subsequently died of hemophagocytic lymphohistiocytosis (considered possibly related to the study drugs). Median intracranial PFS time was 9.7 mo, and the 4-mo intracranial PFS rate was 75%. Extracranial objective response rate was 33% in the 12 evaluable pts with a median response duration of 9.1 mo. Conclusions: Concurrent SRS withnivo/ipi was safe for pts with active NSCLC brain mets. Preliminary analyses of efficacy were encouraging for durable intracranial and extracranial response. Clinical trial information: NCT02696993 .