2530 Background: GL-ONC1 is a genetically engineered vaccinia virus attenuated by insertion of the RUC-GFP (Renilla luciferase and Aequorea green fluorescent protein fusion gene), beta-galactosidase (lacZ) and beta-glucuronidase (gusA) reporter genes into the F14.5L, J2R (thymidine kinase) and A56R (hemaglutinin) loci. A phase I clinical trial of iv GL-ONC1 was pursued to evaluate safety, tolerability, tumour delivery, neutralizing antibody development and anti-tumour activity. Methods: GL-ONC1 was administered to patients with advanced solid tumours at escalating doses (1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 3×10 9 plaque-forming units (pfu) on day 1; 1.667×10 7 and 1.667×10 8 pfu on day 1-3 of a 28-day cycle) using a 3+3 dose escalation design. Green fluorescent protein (GFP) imaging was performed on skin rash and mucosal tumour lesions at baseline and after each cycle. Optional tumour biopsies were obtained for pharmacodynamic and viral delivery evaluation. Results: 27 patients (21 males, median age 60 years) were treated. One of six patients at the 1x10 9 pfu dose level developed a dose-limiting, grade 3 rise in aspartate transaminase levels after a single infusion. Other reported adverse events (grade 1/2) included pyrexia (21), musculoskeletal pain (9), fatigue (8), nausea (7), and vomiting (4). Two patients developed skin rash during the first week of treatment, which appeared green by GFP and were positive to viral plaque assay (VPA). VPA of blood, urine, stool and sputum were negative for viral shedding in all but one patient who had positive shedding for 11 days. Increased neutralizing antibody titres were detected in all tested patients apart from one. Best response by RECIST was stable disease at 48 weeks (1), 24 weeks (3) and 8-12 weeks (5). A patient with squamous cell carcinoma of the tongue had a biopsy after 4 cycles which showed positive IHC staining of vaccinia virus. This is the first time that a virus is shown to be delivered to solid tumour after iv delivery. Conclusions: GL-ONC1 administered iv is well tolerated, with documented colonisation in patient tumour, and preliminary evidence of anti-tumour activity.
We investigated the association between skin rash and plasma creatine kinase (CK) levels in oncology phase I trials. We analysed data from 295 patients treated at our institution within 25 phase I trials which included CK measurements in the protocol. Trials involved drugs targeting EGFR/HER2, m-TOR, VEGFR, SRC/ABL, aurora kinase, BRAF/MEK, PARP, CDK, A5B1 integrin, as well as oncolytic viruses and vascular disrupting agents. Creatine kinase measurements were available for 278 patients. The highest levels of plasma CK during the trial were seen among patients with Grade (G) 2/3 rash (median 249 U l−1) compared with G1 (median 81 U l−1) and no rash (median 55 U l−1) (P<0.001). There was a significant reduction in CK after the rash resolved (mean 264.2 vs 100.1; P=0.012) in 25 patients, where serial CK values were available. In vitro exposure of human keratinocytes to EGFR, MEK and a PI3Kinase/m-TOR inhibitor led to the increased expression of CK-brain and not CK-muscle or mitochondrial-CK. Plasma CK elevation is associated with development of skin rash caused by novel anticancer agents. This should be studied further to characterise different isoforms as this will change the way we report adverse events in oncology phase I clinical trials.
<p>Supplementary Figure 3. Details of a 49 year old patient with platinum-refractory metastatic ovarian cancer and 5 previous lines of chemotherapy treated with oral pictilisib at 100mg once-daily on days 1-21 every 28 days.</p>
<p>Supplementary Figure 4. Association between severity of treatment-related rash and steady-state exposure (day 15 AUC0-24) to pictilisib. (Gr=Grade).</p>
<p>Supplementary Figure 2. Waterfall plot of changes in18F-FDG-PET SUVmax grouped according to pictilisib AUC as assessed by an independent review facility.</p>
Introduction: Accurate gestational age assessment is important in obstetric care ultrasonography. Fetal kidney length is one of the emerging parameter in estimation of fetal gestational age in 3rd trimester. Objectives: Is to the ascertain the precision of ultrasonographic fetal kidney length measurement as a reliable parameter for determination of gestational age in 3rd trimester. Materials and Methods: Cross-sectional observational study was conducted on 152 antenatal women in the 3rd trimester. Gestational age was estimated by early fetal ultrasound measure and last menstrual period. Results: Mean kidney length showed a Pearson’s correlation coefficient of 0.907 and a determination coefficient of 0.822 with GA. The test was significant at P < 0.05. Conclusions: This study confirms that the fetal kidney length measurement for estimating the gestational age accurately in the 3rd trimester.
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