Local Anesthetic-Induced Methemoglobinemia During Pregnancy: A Case Report and Evaluation of Treatment Options.

BACKGROUND: Methemoglobinemia is a well-recognized adverse drug reaction related to the use of certain local anesthetic agents. The mainstay of treatment for methemoglobinemia is i.v. methylene blue, along with provision of supplemental oxygen; however, methylene blue is listed as a category X teratogen. This poses an issue should methemoglobinemia develop during pregnancy. CASE REPORT: A 35-year-old, 20-week and 5-day gravid female was transferred from an outpatient oral surgeon's office for hypoxia. She was undergoing extraction of 28 teeth and was administered an unknown, but "large" quantity of prilocaine during the procedure. Given this exposure, the concern was for methemoglobinemia. This was confirmed with co-oximetry, which showed 34.7% methemoglobin. The initial treatment plan was methylene blue; however, this drug is a category X teratogen. Thus, an interdisciplinary team deliberated and decided on treatment with high-dose ascorbic acid and transfusion of a single unit of packed red blood cells. The patient was managed with noninvasive ventilation strategies and a total of 8 g ascorbic acid. She was discharged on hospital day 3 with no obstetric issues noted. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Intravenous ascorbic acid appears to be a potential alternative to methylene blue in this patient population. The data surrounding teratogenicity of methylene blue are mostly related to intra-amniotic or intra-uterine administration. In life-threatening cases of methemoglobinemia during pregnancy, the benefits of i.v. methylene blue may outweigh the risks.

"I believe this team will change how society views youth in disasters": the EnRiCH Youth Research Team: a youth-led community-based disaster risk reduction program in Ottawa, Canada.

SETTING: The Sendai Framework for Disaster Risk Reduction promotes an "all-of-society" approach to disaster risk reduction (DRR). Since 2013, the EnRiCH Research Lab has implemented a community-based, participatory program to promote youth development and engagement in DRR in Ottawa-Gatineau. The EnRiCH Youth Research Team used an existing community education program called the Enrichment Mini-Course Program as a framework to engage youth in DRR. We aim to share the implementation process and lessons learned from this innovative "all-of-society" approach to DRR. INTERVENTION: The EnRiCH Youth Research Team provides high school and university students with a platform to be heard on disaster and climate change issues. Youth are given opportunities to design and lead knowledge dissemination projects intended to educate members of the community about disaster prevention and preparedness. Students have opportunities to connect with academics, governmental and non-governmental organizations, and public health practitioners to share their ideas on youth participation in DRR in Canada. OUTCOMES: To date, this public health intervention has produced DRR training modules that can be used as curriculum support by teachers, a children's book on earthquake preparedness, an educational video about youth participation in DRR, and several conference presentations. Members of the team have become well versed in disaster preparedness strategies. IMPLICATIONS: This program has demonstrated that youth can contribute to DRR through knowledge mobilization, and support public education about disaster preparedness. Offering this opportunity at a grassroots level can support participation by youth by allowing flexibility in design and adaptation to individual environmental and social contexts.

RéSUMé: CONTEXTE: Le Cadre d'action de Sendai pour la réduction des risques de catastrophe promeut une approche « de la société dans son ensemble ¼ en matière de réduction des risques de catastrophe (RRC). Depuis 2013, le laboratoire de recherche EnRiCH a mis en place un programme participatif communautaire visant à promouvoir la participation et épanouissement des jeunes à la RRC dans la région d'Ottawa-Gatineau. L'équipe de recherche Jeunesse EnRiCH a utilisé un programme d'éducation communautaire déjà existant, le programme de mini-cours d'enrichissement, comme cadre pour engager les jeunes dans la RRC et les sensibiliser à ce sujet. Notre objectif est de partager le processus de mise en œuvre et les leçons tirées de cette approche innovante « de la société dans son ensemble ¼ en RRC. INTERVENTION: L'équipe de recherche Jeunesse EnRiCH fournit aux étudiants du secondaire et universitaires une plateforme pour se faire entendre sur les sujets des catastrophes et des changements climatiques. Les jeunes ont la possibilité de concevoir et de diriger des projets de diffusion des connaissances destinés à éduquer les membres de la communauté en matière de prévention et de préparation aux catastrophes. Ils ont la possibilité de rencontrer des universitaires, des organismes gouvernementaux et non-gouvernementaux et des praticiens de la santé publique pour partager leurs idées sur la participation des jeunes à la RRC au Canada. RéSULTATS: À ce jour, cette intervention de santé publique a produit des modules de formation à la RCC pouvant être utilisés comme matériel éducatif par les enseignants, un livre pour enfants sur la préparation aux tremblements de terre, une vidéo éducative sur la participation des jeunes à la RRC, et plusieurs présentations de conférence. Les membres de l'équipe connaissent bien les stratégies de préparation aux catastrophes. IMPLICATIONS: Ce programme a démontré que les jeunes peuvent contribuer à la RRC par la mobilisation des connaissances et soutenir l'éducation du public en matière de préparation aux catastrophes. Offrir cette opportunité au niveau local peut encourager la participation des jeunes en permettant de la flexibilité dans la mise en oeuvre et une adaptation aux contextes environnementaux et sociaux individuels.

In situ vaccination at a peripheral tumor site augments response against melanoma brain metastases.

BACKGROUND: Immune checkpoint inhibition (ICI) alone is not efficacious for a large number of patients with melanoma brain metastases. We previously established an in situ vaccination (ISV) regimen combining radiation and immunocytokine to enhance response to ICIs. Here, we tested whether ISV inhibits the development of brain metastases in a murine melanoma model. METHODS: B78 (GD2+) melanoma 'primary' tumors were engrafted on the right flank of C57BL/6 mice. After 3-4 weeks, primary tumors were treated with ISV (radiation (12 Gy, day 1), α-GD2 immunocytokine (hu14.18-IL2, days 6-10)) and ICI (α-CTLA-4, days 3, 6, 9). Complete response (CR) was defined as no residual tumor observed at treatment day 90. Mice with CR were tested for immune memory by re-engraftment with B78 in the left flank and then the brain. To test ISV efficacy against metastases, tumors were also engrafted in the left flank and brain of previously untreated mice. Tumors were analyzed by quantitative reverse transcription-PCR, immunohistochemistry, flow cytometry and multiplex cytokine assay. RESULTS: ISV+α-CTLA-4 resulted in immune memory and rejection of B78 engraftment in the brain in 11 of 12 mice. When B78 was engrafted in brain prior to treatment, ISV+α-CTLA-4 increased survival compared with ICI alone. ISV+α-CTLA-4 eradicated left flank tumors but did not elicit CR at brain sites when tumor cells were engrafted in brain prior to ISV. ISV+α-CTLA-4 increased CD8+ and CD4+ T cells in flank and brain tumors compared with untreated mice. Among ISV + α-CTLA-4 treated mice, left flank tumors showed increased CD8+ infiltration and CD8+:FOXP3+ ratio compared with brain tumors. Flank and brain tumors showed minimal differences in expression of immune checkpoint receptors/ligands or Mhc-1. Cytokine productions were similar in left flank and brain tumors in untreated mice. Following ISV+α-CTLA-4, production of immune-stimulatory cytokines was greater in left flank compared with brain tumor grafts. CONCLUSION: ISV augmented response to ICIs in murine melanoma at brain and extracranial tumor sites. Although baseline tumor-immune microenvironments were similar at brain and extracranial tumor sites, response to ISV+α-CTLA-4 was divergent with reduced infiltration and activation of immune cells in brain tumors. Additional therapies may be needed for effective antitumor immune response against melanoma brain metastases.

The Promotion of 'Grab Bags' as a Disaster Risk Reduction Strategy.

INTRODUCTION: An all-of-society approach to disaster risk reduction emphasizes inclusion and engagement in preparedness activities. A common recommendation is to promote household preparedness through the preparation of a 'grab bag' or 'disaster kit', that can be used to shelter-in-place or evacuate. However, there are knowledge gaps related to how this strategy is being used around the world as a disaster risk reduction strategy, and what evidence there is to support recommendations. METHODS: In this paper, we present an exploratory study undertaken to provide insight into how grab bag guidelines are used to promote preparedness in Canada, China, England, Japan, and Scotland, and supplemented by a literature review to understand existing evidence for this strategy. RESULTS: There are gaps in the literature regarding evidence on grab bag effectiveness. We also found variations in how grab bag guidelines are promoted across the five case studies. DISCUSSION:  While there are clearly common items recommended for household grab bags (such as water and first aid kits), there are gaps in the literature regarding: 1) the evidence base to inform guidelines; 2) uptake of guidelines; and 3) to what extent grab bags reduce demands on essential services and improve disaster resilience.

Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites.

In situ vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an in situ vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the "primary" tumor would induce a systemic antitumor response causing regression of the "secondary" tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated "primary" tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Treg). Transgenic "DEREG" mice or IgG2a anti-CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT + IT-IC delivered to the primary tumor. We observed reciprocal tumor specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT + IT-IC together with systemic administration of Treg-depleting anti-CTLA-4 resulted in a renewed in situ vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of in situ vaccination and demonstrate clinically viable approaches to overcome this effect. Untreated tumor sites antagonize the systemic and local antitumor immune response to an in situ vaccination regimen. This effect is radiation sensitive and may be mediated by tumor-specific regulatory T cells harbored in the untreated tumor sites. Cancer Immunol Res; 6(7); 825-34. ©2018 AACR.

In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments.

Interest in combining radiotherapy and immune checkpoint therapy is growing rapidly. In this study, we explored a novel combination of this type to augment antitumor immune responses in preclinical murine models of melanoma, neuroblastoma, and head and neck squamous cell carcinoma. Cooperative effects were observed with local radiotherapy and intratumoral injection of tumor-specific antibodies, arising in part from enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We could improve this response by combining radiation with intratumoral injection of an IL2-linked tumor-specific antibody (termed here an immunocytokine), resulting in complete regression of established tumors in most animals associated with a tumor-specific memory T-cell response. Given the T-cell response elicited by combined local radiation and intratumoral immunocytokine, we tested the potential benefit of adding this treatment to immune checkpoint blockade. In mice bearing large primary tumors or disseminated metastases, the triple-combination of intratumoral immunocytokine, radiation, and systemic anti-CTLA-4 improved primary tumor response and animal survival compared with combinations of any two of these three interventions. Taken together, our results show how combining radiation and intratumoral immunocytokine in murine tumor models can eradicate large tumors and metastases, eliciting an in situ vaccination effect that can be leveraged further by T-cell checkpoint blockade, with immediate implications for clinical evaluation. Cancer Res; 76(13); 3929-41. ©2016 AACR.