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Background and aim: We determined to investigate the incidence and clinical impact of new cerebral microbleeds after intravenous thrombolysis in patients with acute stroke. Methods: The THAWS was a multicenter, randomized trial to study the efficacy and safety of intravenous thrombolysis with alteplase in patients with wake-up stroke or unknown onset stroke. Prescheduled T2*-weighted imaging assessed cerebral microbleeds at three time points: baseline, 22–36 h, and 7–14 days. Outcomes included new cerebral microbleeds development, modified Rankin Scale (mRS) ≥3 at 90 days, and change in the National Institutes of Health Stroke Scale (NIHSS) score from 24 h to 7 days. Results: Of all 131 patients randomized in the THAWS trial, 113 patients (mean 74.3 ± 12.6 years, 50 female, 62 allocated to intravenous thrombolysis) were available for analysis. Overall, 46 (41%) had baseline cerebral microbleeds (15 strictly lobar cerebral microbleeds, 14 mixed cerebral microbleeds, and 17 deep cerebral microbleeds). New cerebral microbleeds only emerged in the intravenous thrombolysis group (seven patients, 11%) within a median of 28.3 h, and did not additionally increase within a median of 7.35 days. In adjusted models, number of cerebral microbleeds (relative risk (RR) 1.30, 95% confidence interval (CI): 1.17–1.44), mixed distribution (RR 19.2, 95% CI: 3.94–93.7), and cerebral microbleeds burden ≥5 (RR 44.9, 95% CI: 5.78–349.8) were associated with new cerebral microbleeds. New cerebral microbleeds were associated with an increase in NIHSS score (p = 0.023). Treatment with alteplase in patients with baseline ≥5 cerebral microbleeds resulted in a numerical shift toward worse outcomes on ordinal mRS (median [IQR]; 4 [3–4] vs. 0 [0–3]), compared with those with <5 cerebral microbleeds (common odds ratio 17.1, 95% CI: 0.76–382.8). The association of baseline ≥5 cerebral microbleeds with ordinal mRS score differed according to the treatment group (p interaction = 0.042). Conclusion: New cerebral microbleeds developed within 36 h in 11% of the patients after intravenous thrombolysis, and they were significantly associated with mixed-distribution and ≥5 cerebral microbleeds. New cerebral microbleeds development might impede neurological improvement. Furthermore, cerebral microbleeds burden might affect the effect of alteplase. [ABSTRACT FROM AUTHOR]

Background: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is undertaking a major revision of ICH E6 Good Clinical Practice (GCP) decided to involve external stakeholders in ICH-GCP renovation. Activities such as surveys and public conferences have taken place in the United States, European Union, and Japan. For stakeholder engagement in Japan, a designated research group conducted a survey of academic stakeholders. Methods: A total of 105 academic stakeholders from 18 institutions responded to the survey. The research group developed recommendations reflecting the survey results and the opinions from patients and the public. Results: The survey showed the top four principles needing renovation were (i) informed consent (Chapter 2.9, 12.4% of respondents believed it needed renovation), (ii) systems for quality assurance (Chapter 2.13, 9.5%), (iii) information on an investigational product (Chapter 2.4, 5.7%), and (iv) procedures on clinical trial information (Chapter 2.10, 5.7%). The top three sections identified as needing renovation were: (i) informed consent (Chapter 4.8, 27.6%), (ii) monitoring (Chapter 5.18, 22.9%), and (iii) composition, functions, and operations of the ethics committee (Chapter 3.2, 14.3%). Recommendations included clarification of ICH-GCP's scope, proportionality in various aspects of clinical trials, diversity and liquidity of ethics committee members, modernization of informed consent procedures, variations in monitoring, and regulatory grade when using real-world data. Conclusion: The recommendations from Japanese investigators and patients have been submitted to the ICH E6 Expert Working Group, which will strengthen the robustness of the GCP renovation. [ABSTRACT FROM AUTHOR]

Background: Neurological deterioration (ND) has a major influence on the prognosis of intracerebral hemorrhage (ICH); however, factors associated with ND occurring after 24 h of ICH onset are unknown. Methods: We performed exploratory analyses of data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial, which compared intensive and standard blood pressure lowering treatment in ICH. NDs were captured on the adverse event case report form. Logistic regression analysis was performed to examine the independent predictors of late ND. Results: Among 1,000 participants with acute ICH, 82 patients (8.2%) developed early ND (≤24 h), and 64 (6.4%) had late ND. Baseline hematoma volume (adjusted OR [aOR] per 1-cm3 increase 1.04, 95% CI 1.02–1.06, p < 0.0001), hematoma volume increase in 24 h (aOR 2.24, 95% CI 1.23–4.07, p = 0.008), and the presence of intraventricular hemorrhage (IVH; aOR 2.38, 95% CI 1.32–4.29, p = 0.004) were independent predictors of late ND (vs. no late ND). Late ND was a significant risk factor for poor 90-day outcome (OR 3.46, 95% CI 1.82–6.56). No statistically significant difference in the incidence of late ND was noted between the 2 treatment groups. Conclusions: Initial hematoma volume, early hematoma volume expansion, and IVH are independent predictors of late ND after ICH. Intensive reduction in the systolic blood pressure level does not prevent the development of late ND. [ABSTRACT FROM AUTHOR]

Background: Postoperative cancer recurrence is a major problem following curative surgery. In a previous retrospective study of lung cancer surgery, we reported that administration of atrial natriuretic peptide (ANP) during the perioperative period reduced postoperative recurrence. We demonstrated that ANP inhibited the adhesion of cancer cells to vascular endothelium as a vasoprotective action. The objective of this study is to evaluate the effects of ANP on the incidence of postoperative cancer recurrence in lung cancer surgery.Methods/design: The present study is a multicenter, randomized trial with two parallel groups of patients with lung cancer comparing surgery alone and surgery with ANP administration for 3 days during the perioperative period. A total of 500 patients will be enrolled from 10 Japanese institutions. The primary endpoint is 2-year relapse-free survival (RFS). The secondary endpoints are 2-year cancer-specific RFS, 5-year RFS, overall survival, the incidence of postoperative complications, and the completion rate of ANP treatment.Discussion: The principal question addressed in this trial is whether ANP with its vasoprotective action can reduce cancer recurrence following lung cancer surgery.Trial Registration: UMIN Clinical Trials Registry identifier: UMIN000018480 . Registered on 31 July 2015. [ABSTRACT FROM AUTHOR]

Rationale Because of lack of information regarding timing of stroke, patients who suffer stroke during sleep are generally ineligible for intravenous thrombolysis, although many of these patients could potentially recover with this treatment. Magnetic resonance image findings with positive diffusion-weighted imaging and no marked parenchymal hyperintensity on fluid-attenuated inversion recovery (negative pattern) can identify acute ischemic stroke patients within 4·5 h from symptom onset. Aims The THrombolysis for Acute Wake-up and unclear-onset Strokes with alteplase at 0·6 mg/kg trial aims to determine the efficacy and safety of intravenous thrombolysis with alteplase at 0·6 mg/kg body weight, the approved dose for Japanese stroke patients, using magnetic resonance image-based selection in ischemic stroke patients with unclear time of symptom onset, and compare findings with standard treatment. Design This is an investigator-initiated, multicenter, prospective, randomized, open-treatment, blinded-end-point clinical trial. The design is similar to the Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke trial. Patients with unclear-onset time of stroke symptoms beyond 4·5 h and within 12 h after the time of the last-known-well period and within 4·5 h after symptom recognition, who showed a negative fluid-attenuated inversion recovery pattern, are randomized to either intravenous thrombolysis or standard treatment. Study outcomes The primary efficacy end-point is modified Rankin Scale 0-1 at 90 days. The safety outcome measures are symptomatic intracranial hemorrhage at 22-36 h, and major bleeding and mortality at 90 days. Discussion This trial may help determine if low-dose alteplase at 0·6 mg/kg should be recommended as a routine clinical strategy for ischemic stroke patients with unclear-onset time. [ABSTRACT FROM AUTHOR]