Phase Ib Trial of Mutant Herpes Simplex Virus G207 Inoculated Pre-and Post-tumor Resection for Recurrent GBM

We have previously demonstrated safety of G207, a doubly mutated (deletion of both γ₁34.5 loci, insertional inactivation of U_L39) herpes simplex virus (HSV) for patients stereotactically inoculated in enhancing portions of recurrent malignant gliomas. We have now determined safety of two inoculations of G207, before and after tumor resection. Inclusion criteria were histologically proven recurrent malignant glioma, Karnofsky score ≥70, and ability to resect the tumor without ventricular system breach. Patients received two doses of G207 totaling 1.15 × 10⁹ plaque-forming units with 13% of this total injected via a catheter placed stereotactically in the tumor. Two or five days later, tumor was resected en bloc with catheter in place. The balance of G207 dose was injected into brain surrounding the resection cavity. Six patients with recurrent glioblastoma multiforme were enrolled. Two days after the second G207 inoculation, one patient experienced transient fever, delirium, and hemiparesis, which entirely resolved on high-dose dexamethasone. No patient developed HSV encephalitis or required treatment with acyclovir. Radiographic and neuropathologic evidence suggestive of antitumor activity is reported. Evidence of viral replication was demonstrated. G207 appears safe for multiple dose delivery, including direct inoculation into the brain surrounding tumor resection cavity.     

Methotrexate and cytarabine inhibit progression of human lymphoma in NOD/SCID mice carrying a mutant dihydrofolate reductase and cytidine deaminase fusion gene.

An SFG-based retroviral bicistronic vector containing a double-mutant dihydrofolate reductase-cytidine deaminase fusion cDNA (F/S DHFR-CD) with IRES-eGFP confers resistance to both methotrexate (MTX) and cytarabine (ara-C). Two weeks after transplantation with marrow transduced with either a fusion or a control gene (eGFP-IRES-NeoR), human lymphoma (SKI-DLCL-1) cells were injected sc into the flanks of nonobese diabetic/severe combined immune deficiency mice. In mock-transplanted mice, maximal tolerated dose (MTD) of posttransplant MTX/ara-C (15/10 mg/kg/day, x3) was unable to control tumor growth. Transfer of the fusion gene allowed doses of MTX/ara-C (25/15 mg/kg/day, x4) twofold higher than the MTD to be tolerated. The tumor burden defined the efficiency of posttransplant chemotherapy; early treatment, 48 h after tumor inoculation, provided tumor-free survival, while starting treatment after having palpable tumor growth (7 days) delayed tumor growth a median time of 28 days. In addition, the early treated group had higher gene expression in peripheral blood and marrow cells than the late treated group (P < 0.05), suggesting that early treatment allowed for enrichment of transduced marrow progenitors. These results encourage clinical studies using this retroviral fusion gene construct.     

In vitro activities of 2,4-diaminoquinazoline and 2,4-diaminopteridine derivatives against Plasmodium falciparum

The activities of 28 6-substituted 2,4-diaminoquinazolines, 2,4-diamino-5,6,7,8-tetrahydroquinazolines, and 2,4-diaminopteridines against Plasmodium falciparum were tested. The 50% inhibitory concentrations (IC(50)s) of six compounds were <50 nM, and the most potent compound was 2,4-diamino-5-chloro-6-[N-(2,5-dimethoxybenzyl)amino]quinazoline (compound 1), with an IC(50) of 9 nM. The activity of compound 1 was potentiated by the dihydropteroate synthase inhibitor dapsone, an indication that these compounds are inhibitors of dihydrofolate reductase. Further studies are warranted to assess the therapeutic potential of this combination in vivo.     

Avances del Modelo Educativo para Desarrollar Actividades Profesionales Confiables (MEDAPROC)☆

The Educational Model to Develop Entrustable Professional Activities (MEDAPROC) arises as a response to the implementation of competency-based education. It is a multidisciplinary project based on interpretative epistemology, the constructivist paradigm, the transformations of the national health system, and the context of the current practice of medicine. Its purpose is to encourage the acquisition of essential knowledge, skills, and attitudes by the medical student. It integrates the international trend of the entrustable professional activities and converts them into entrustable professional activities (APROC). MEDAPROC proposes that the development of the APROC be promoted in an inverse manner, from the profile of the graduate to the beginning of the undergraduate studies. Therefore, it is involved in several phases of the learning and teaching process (planning, didactics, assessment, and feedback) through projects to implement didactic strategies and assessment resources, with the support of teacher training, educational research, and technology. Its aim is to improve medical and health sciences education, with the firm purpose of making a positive change in the health care quality from the educational environment.     

Parental presence at anaesthesia induction: A systematic review

This systematic review assessed the effectiveness of parental presence for children undergoing surgical or diagnostic procedures under general anaesthesia (such as bronchoscopy, laryngoscopy and laparoscopy). Randomized and quasi randomized trials with healthy children scheduled for elective diagnostic and surgical procedures under general anaesthesia (age range 0–16 years) where the intervention was parental presence at anaesthesia induction were included. A comprehensive literature search was conducted using electronic databases and the reference lists of included studies. The Cochrane collaboration's tool for assessing risk of bias was used for assessment of risk of bias. The Review Manager software was used to analyse and synthesize data. A random‐effect meta‐analysis was used when there was evidence of clinical and/or statistical heterogeneity. Of the 102 citations identified, nine trials involving 1021 children were eligible for inclusion. Only four were sufficient to be included in the meta‐analysis. There was no statistically significant difference on average in the level of anxiety in children and their parents either at separation or at induction between children allocated to parental presence and those allocated to no presence, premedication or parental presence plus premedication groups. Significant debate still surrounds this issue, and future trials should focus on the use of reliable and validated tools in assessing outcome measures.     

Keeping newborns warm: beliefs,practices and potential for behaviour change in rural Ghana

Objectives This study aimed to collect data on thermal care practices in rural Ghana to inform the design of a community newborn intervention. Methods All 635 women who delivered in six districts in Ghana in the first 2 weeks of December 2006 were interviewed about immediate newborn care. Qualitative data on thermal care practices and barriers and facilitators to behaviour change were collected from recently delivered/pregnant women, birth attendants/grandmothers, and husband through birth narratives, in‐depth interviews and focus group discussion. Results Respondents knew that keeping the baby warm was essential for health but 71% of babies born at home had delayed drying, 79% delayed wrapping, 93% early bathing and 10% were placed skin‐to‐skin. Birth attendants were usually in charge of mother and baby immediately after birth. Delays in drying/wrapping were linked to leaving the baby unattended until the placenta was delivered. Early bathing was linked to reducing body odour in later life, shaping the baby’s head, and helping the baby sleep and feel clean. Respondents thought that changing bathing behaviours would be difficult, especially as babies are bathed early in facilities. The concept of skin‐to‐skin care was easily understood and most women said they would try it if it was good for the baby. Conclusion Thermal care is a key component of community newborn interventions, the design of which should be based on an understanding of current behaviours and beliefs. Formative research can help select focus behaviours, decide who to include in interventions, ensure consistent messages and determine what messages and approaches are needed to overcome behaviour change barriers.     

Activity of Crizotinib (PF02341066), a Dual Mesenchymal-Epithelial Transition (MET) and Anaplastic Lymphoma Kinase (ALK) Inhibitor,in a Non-small Cell Lung Cancer Patient with De Novo MET Amplification

Crizotinib is a dual MET and ALK inhibitor. Currently, clinical development of crizotinib is focused primarily on ALK rearranged non-small cell lung cancer (NSCLC). Here we report an NSCLC patient with de novo MET amplification but no ALK rearrangement who achieved a rapid and durable response to crizotinib indicating is also a bona fide MET inhibitor.