AGO‐OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front‐line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib ...demonstrated significantly improved progression‐free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB–IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2–21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval CI 0.83–1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh‐risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75–0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.
What's new?
Primary results from the randomised phase III AGO‐OVAR 12 trial comparing nintedanib (a triple angiokinase inhibitor) with placebo given in combination with chemotherapy and then continued as maintenance therapy in patients with newly diagnosed advanced ovarian carcinoma demonstrated a significant improvement in progression‐free survival with nintedanib. However, as reported in this paper, final overall survival (OS) results showed that the addition of nintedanib had no impact on OS. These results do not, therefore, support use of nintedanib in ovarian cancer.
Background: The aim of this study was to assess changes in hemostasis and associated outcome of hospitalized patients with COVID-19 infection and mild hypoxemia. Methods: Adult patients with COVID-19 ...infection and hypoxemia admitted to ICU were included in this prospective observational study. The primary outcome was defined as an unfavorable course of the disease if a patient: (1) developed a thromboembolic event while receiving anticoagulation prophylaxis, (2) had prolonged ICU stay, or (3) died. Demographic data, laboratory parameters and thromboelastometry (ROTEM) test results were collected. Results: Twenty-five patients were recruited into the study. There were 16 patients with an unfavorable course of the disease. Compared to the 9 patients in the favorable course group, patients with an unfavorable course had a lower platelet count, median difference of 154 (95% CI, 26 to 223 x10.sup.9/L), P = 0.012, and lower clot firmness parameters in EXTEM assay: amplitude at 20 minutes (A20), median difference of 7 (95% CI, 2 to 11) P = 0.006, maximum clot firmness (MCF), median difference of 6 (95% CI, 3 to 10) P = 0.006 and area under the curve (AUC) with a median difference of 671 (95% CI, 244 to 1029) P = 0.005. They also demonstrated suppression of fibrinolysis: higher lysis index 60, median difference of -3 (95% CI, -6 to 0), P = 0.023. Results of functional fibrinogen (FIBTEM) assay were similar between the groups. Conclusion: The platelet count and the results of EXTEM assay, but not FIBTEM assay, were associated with the difference in clinical outcome among patients with COVID-19 infection and hypoxemia. The role of platelets in the outcome of COVID-19 infection calls for further investigation. Future studies on adjusting anticoagulant therapy based on the results of viscoelastic testing may be beneficial. Keywords: intensive care unit, thromboelastometry, coronavirus disease 2019, hypoxemia, hemostasis, thrombosis, recovery, mortality
This article analyzes local government fiscal sustainability as a common-pool resource (CPR) problem. Comparing the experiences of Los Angeles County, San Bernardino City, and San Bernardino County, ...California, the analysis applies a framework developed from three decades of CPR research to show the importance of six micro-situational variables—communications with the full set of participants, known reputations of participants, high marginal per capita return, entry or exit capabilities, longer time horizon, and agreed-upon sanctioning capabilities—in shaping collective action dynamics and building the trust and reciprocity among stakeholders needed to achieve fiscal sustainability. The underlying contextual conditions for these micro-situational variables vary based on specific socioeconomic and political settings, but the findings suggest that institutions and processes can be designed based on several well-tested principles in CPR governance to encourage stakeholders to look beyond their immediate self-interests and make decisions that account for the community's long-term fiscal sustainability.
With greater global economic competition and a heavy burden of public debt, America's communities need visionary leaders who can develop new strategies to leverage our assets more effectively and ...promote collective actions designed to achieve results that create collective goods.
Implementation of new large-scale infrastructure projects and systems continues to be elusive. Using a case study approach, this article suggests that leaders who acted strategically, mobilized ...resources and assets that provided outcomes that were then linked to payment by users in a business plan, and satisfied multiple objectives were successful. To realize this success, new institutional designs or “rules of the game” are developed for the organizations involved in implementing the project. Implementation is possible when leaders are willing to change how they approached solving problems.
Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). The HTLV-1 oncoprotein Tax plays an important role in ATL pathogenesis. ATL ...carries a poor prognosis due to chemotherapy resistance, stressing the need for alternative therapies. Here, we investigate the preclinical efficacy of the synthetic retinoid ST1926 in ATL and peripheral T-cell lymphomas. Clinically achievable concentrations of ST1926 induced a dramatic inhibition of cell proliferation in malignant T-cell lines and primary ATL cells with minimal effect on resting or activated normal lymphocytes. ST1926 induced apoptosis, DNA damage, and upregulation of p53 proteins in malignant T cells, whereas it caused an early downregulation of Tax proteins in HTLV-1–positive cells. In murine ATL, oral treatment with ST1926 prolonged survival and reduced leukemia cell infiltration, white blood cell counts, and spleen mass. In spleens of ST1926-treated animals, p53 and p21 proteins were upregulated, poly (ADP-ribose) polymerase was cleaved, and Tax transcripts were reduced. These results highlight the promising use of ST1926 as a targeted therapy for ATL.
•The synthetic retinoid ST1926 induces apoptosis of ATL cells and prolongs survival of ATL mice.•At the molecular level, ST1926 causes early DNA damage, upregulates p53, and downregulates Tax expression.
Background
Ablation index (AI) is a new lesion quality marker that has been demonstrated to allow a high single‐procedure arrhythmia‐free survival in single‐center studies. This prospective, ...multi‐center study was designed to evaluate the reproducibility of pulmonary vein (PV) isolation guided by the AI.
Methods
A total of 490 consecutive patients with paroxysmal (80.4%) and persistent AF underwent first time PV isolation and were divided in four study groups according to operator's preference in choosing the ablation catheter (a contact force (ST) or contact force surround flow (STSF) catheter) and the AI setting (330‐450 or 380‐500 at anterior wall or posterior wall, respectively).
Results
At 12 months a high rate of freedom from AF recurrences was observed in patients with both paroxysmal and persistent AF (91% vs 83.3%; P = .039). There was no difference in the rate of AF recurrence among the four study groups (4.5% in group ST330‐450, 12.2% in group ST 380‐500, 14.9% in group STSF330‐450, 9.4% in group STSF380‐500; P = .083). Recurrence was also similar between patients treated with a ST (8%) or STSF catheter (12.1%; P = .2), and within patients targeting an AI settings of 330 to 450 (10.9%) or 380 to 500 (10.3%; P = .64). In patients with paroxysmal AF, there was no difference (P = .12) in the 1‐year freedom from AF recurrence among 14 operators that performed ≥10 ablation procedure.
Conclusions
An ablation protocol respecting strict criteria for contiguity and quality lesion resulted in high rate of 1‐year freedom from AF recurrence, irrespective of the ablation catheters, AI settings, and operator.
Digital mammography systems allow manipulation of fine differences in image contrast by means of image processing algorithms. Different display algorithms have advantages and disadvantages for the ...specific tasks required in breast imaging-diagnosis and screening. Manual intensity windowing can produce digital mammograms very similar to standard screen-film mammograms but is limited by its operator dependence. Histogram-based intensity windowing improves the conspicuity of the lesion edge, but there is loss of detail outside the dense parts of the image. Mixture-model intensity windowing enhances the visibility of lesion borders against the fatty background, but the mixed parenchymal densities abutting the lesion may be lost. Contrast-limited adaptive histogram equalization can also provide subtle edge information but might degrade performance in the screening setting by enhancing the visibility of nuisance information. Unsharp masking enhances the sharpness of the borders of mass lesions, but this algorithm may make even an indistinct mass appear more circumscribed. Peripheral equalization displays lesion details well and preserves the peripheral information in the surrounding breast, but there may be flattening of image contrast in the nonperipheral portions of the image. Trex processing allows visualization of both lesion detail and breast edge information but reduces image contrast.
Thromboembolic events are important complications of pulmonary vein isolation (PVI) procedures, occurring in up to 2.8% of patients. In this study, we report the incidence of char formation and ...embolic events with different anticoagulation protocols prospectively changed to reduce such complication.
Methods: A total of 785 patients (mean age: 54 years, 83.5% male) underwent catheter‐based PVI for treatment of drug refractory, symptomatic atrial fibrillation (AF). PVI was performed utilizing different strategies including radiofrequency (RF) using temperature control energy delivery and RF using intracardiac echocardiography (ICE)‐guided power titration. Patients were divided based on the anticoagulation protocol into three groups: in group 1 (194 patients), activation coagulation time (ACT) was maintained between 250 and 300 seconds; in group 2 (180 patients), ACT was maintained between 300 and 350 seconds plus the IV infusion of eptifibatide (135 μg/kg bolus + 0.5 μg/kg/min); and in group 3 (411 patients), ACT was maintained between 350 and 400 seconds.
Results: Char formation was detected in 69 patients of group 1, 5 of group 2, and 8 of group 3. An embolic event was observed in 7 patients of group 1, 3 of group 2, and 2 of group 3 (P = 0.01; group 1 vs group 3). Higher degree of anticoagulation with heparin was associated with a reduced incidence of embolic events even after removing the patients undergoing ICE‐guided ablation (P = 0.04).
Conclusion: More aggressive anticoagulation with heparin reduced periprocedural embolic events. The use of platelet inhibition does not have incremental beneficial effect. None of the anticoagulation protocol abolished char formation.
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