Background and Purpose-Granulocyte colony-stimulating factor (G-CSF) is a promising stroke drug candidate. The present phase IIa study assessed safety and tolerability over a broad dose range of G-CSF doses in acute ischemic stroke patients and explored outcome data. Methods-Four intravenous dose regimens (total cumulative doses of 30 -180 g/kg over the course of 3 days) of G-CSF were tested in 44 patients in a national, multicenter, randomized, placebo-controlled dose escalation study (NCT00132470; www.clinicaltrial.gov). Main inclusion criteria were a 12-hour time window after stroke onset, infarct localization to the middle cerebral artery territory, a baseline National Institutes of Health Stroke Scale range of 4 to 22, and presence of diffusion-weighted imaging/perfusion-weighted imaging mismatch. Results-Concerning the primary safety end points, we observed no increase of thromboembolic events in the active treatment groups, and no increase in related serious adverse events. G-CSF led to expected increases in neutrophils and monocytes that resolved rapidly after end of treatment. We observed a clinically insignificant drug-related decrease of platelets. As expected from the low number of patients, we did not observe significant differences in clinical outcome in treatment vs. placebo. In exploratory analyses, we observed an interesting dose-dependent beneficial effect of treatment in patients with DWI lesions Ͼ14 -17 cm 3 . Conclusions-We conclude that G-CSF was well-tolerated even at high dosages in patients with acute ischemic stroke, and that a substantial increase in leukocytes appears not problematic in stroke patients. In addition, exploratory analyses suggest treatment effects in patients with larger baseline diffusion-weighted imaging lesions. The obtained data provide the basis for a second trial aimed to demonstrate safety and efficacy of G-CSF on clinical end points. (Stroke. 2010; 41:2545-2551.)Key Words: clinical trial Ⅲ granulocyte colony-stimulating factor Ⅲ hematopoietic growth factor Ⅲ leukocytes G ranulocyte-colony stimulating factor (G-CSF) is a growth factor of approximately 20 kDa that was initially identified as the main driver for generation of neutrophilic granulocytes and is in widespread clinical use for the treatment of chemotherapy-associated neutropenia. We and others have uncovered that G-CSF also acts as a potent neuronal growth factor. G-CSF acts antiapoptotically on neurons, stimulates neurogenesis, and enhances vessel reformation in the ischemic brain ( 1 ). Also, G-CSF is released by neurons in response to cerebral ischemia. 1 Systemically administered G-CSF passes the intact blood-brain barrier and decreases infarct size ( 2 ). Meta-analyses of the existing data and comparison to other experimental stroke drugs strengthen confidence in the efficacy of G-CSF in rodent models of stroke. 3,4 Importantly, G-CSF not only is acutely protective but also improves functional recovery after stroke, even when treatment is initiated at delayed time intervals. 5 The main advantages o...
BackgroundG-CSF has been shown in animal models of stroke to promote functional and structural regeneration of the central nervous system. It thus might present a therapy to promote recovery in the chronic stage after stroke.MethodsHere, we assessed the safety and tolerability of G-CSF in chronic stroke patients with concomitant vascular disease, and explored efficacy data. 41 patients were studied in a double-blind, randomized approach to either receive 10 days of G-CSF (10 µg/kg body weight/day), or placebo. Main inclusion criteria were an ischemic infarct >4 months prior to inclusion, and white matter hyperintensities on MRI. Primary endpoint was number of adverse events. We also explored changes in hand motor function for activities of daily living, motor and verbal learning, and finger tapping speed, over the course of the study.ResultsAdverse events (AEs) were more frequent in the G-CSF group, but were generally graded mild or moderate and from the known side-effect spectrum of G-CSF. Leukocyte count rose after day 2 of G-CSF dosing, reached a maximum on day 8 (mean 42/nl), and returned to baseline 1 week after treatment cessation. No significant effect of treatment was detected for the primary efficacy endpoint, the test of hand motor function.ConclusionsThese results demonstrate the feasibility, safety and reasonable tolerability of subcutaneous G-CSF in chronic stroke patients. This study thus provides the basis to explore the efficacy of G-CSF in improving chronic stroke-related deficits.Trial RegistrationClinicalTrials.gov NCT00298597
Despite 410 years of routine human epidermal growth factor receptor 2 (HER2) testing in breast cancer, testing quality is still an issue. Guidelines recommend assessing HER2 positivity rates as a quality indicator; however, the extent to which patient-or tumor-related factors influence HER2 positivity is still unknown. The present study analyzed these influences to identify pathology centers with HER2 positivity rates unexplained by patient-or tumor-related factors. This observational, prospective study monitored routine HER2 testing at 57 institutes of pathology in Germany (January 2013-August 2014). Data collected included HER2 test result, patient-and tumorrelated factors, sample source, and method of sample retrieval. Factors influencing HER2 positivity rates were identified by multiple logistic regression. Individual center effects were assessed in an extended multiple logistic regression model by their statistical significance after adjusting for the combined effect of patient-or tumorrelated covariates and multiple testing. Analyses included 15 332 invasive breast cancer samples. Histologic grade showed the strongest influence on HER2 positivity, followed by hormone receptor status, histologic subtype, age, and nodal status (all Po 0.0001). The overall HER2 positivity rate across centers was 14.4% (range 7.1-27.3%). A statistically significant center effect on the HER2 positivity rate was identified for three centers (Po 0.05), with a trend toward a center effect for a further three (P o0.2). This study, the first of its kind, highlights that assessing HER2 testing quality with HER2 positivity rates should include standardized assessment of patient-or tumor-related characteristics to identify centers with HER2 testing quality issues more effectively. As treatment options for HER2-positive breast cancer continue to evolve, identifying the right patients is key. Overexpression of the human epidermal growth factor receptor 2 (HER2) protein or amplification of the HER2 gene occurs in~15-20% of all breast cancers. 1 HER2-positive breast cancer has a worse prognosis than HER2-negative disease, having an increased risk of recurrence and a more aggressive disease course. 2-4 HER2 is a prognostic biomarker predictive for the response to HER2-targeted therapies including the recombinant monoclonal antibodies trastuzumab and pertuzumab, and the antibody-drug conjugate ado-trastuzumab emtansine, all of which specifically target HER2 and are effective treatments for HER2-positive breast Correspondence: Professor J
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