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Abstract Background Since the last guidance was published by the Canadian Thoracic Society, there have been several advances in the clinical management of severe asthma. To gain a better understanding of the current standards of care and treatment patterns of patients, the CASCADE practice reflective program was established to conduct a real-world analysis of severe asthma management among specialists in Canada with a goal of identifying areas of opportunity to enhance patient management and outcomes. Methods The CASCADE program was a two-part practice reflective and assessment program delivered through an on-line portal for selected specialists (Respirologists and Allergists) in Canada. The program consisted of a one-time overview survey of physician practice to establish overall practice parameters, followed by a review of at least 5 severe asthma patients to establish the current landscape of severe asthma management. Results The program collected practice overview surveys from 78 specialists (52 Respirologists, 24 Allergists, and 2 General practice physicians with an interest in respiratory disease) in 8 provinces. Practices included a variety of types in both large metropolitan centres and smaller regional settings. There were 503 patients reviewed and included in the program. Most (65%) patients were currently using a biologic treatment, 30% were biologic naive, and 5% had used a biologic treatment in the past. Most patients (53%) were reported to have mixed allergic and eosinophilic phenotypes, despite a perception that allergic, eosinophilic and mixed phenotypes were evenly balanced in the physician practice. Overall, patients currently treated with biologic agents had parameters suggesting higher control and were more satisfied with treatment. However, there was less than optimal treatment satisfaction for more than half of all patients, particularly for those patients not treated with a biologic agent. Conclusions Phenotyping is hampered by poor availability for several assessments, and the full range of treatments are not currently fully utilized, partly due to physician familiarity with the agents and partly due to prescribing restrictions. Even when treated with biologic agents, patient satisfaction can still be improved.

BackgroundVascular dementia (VaD) is a complex neurodegenerative disorder. We previously found that treatment of VaD in middle-aged male rats subjected to multiple microinfarction (MMI) with AV-001, a Tie2 receptor agonist, significantly improves cognitive function. Age and sex affect the development and response of VaD to therapeutic intervention. Thus, the present study investigated the therapeutic effect of AV-001 on VaD in aged female rats subjected to MMI.MethodsFemale 18-month-old Wistar rats were subjected to MMI by injecting either 1,000 (low dose, LD-MMI) or 6,000 (high dose, HD-MMI) cholesterol crystals of size 70–100 μm into the right internal carotid artery. AV-001 (1 μg/Kg, i.p.) was administered once daily after MMI for 1 month, with treatment initiated 1 day after MMI. A battery of behavioral tests to examine sensorimotor and cognitive functions was performed at 21–28 days after MMI. All rats were sacrificed at 1 month after MMI.ResultsAged female rats subjected to LD-MMI exhibit severe neurological deficits, memory impairment, and significant white matter (WM) and oligodendrogenesis injury in the corpus callosum compared with control rats. HD-MMI in aged female rats induces significant anxiety- and depression-like behaviors, which were not detected in LD-MMI aged female rats. Also, HD-MMI induces significantly increased WM injury compared to LD-MMI. AV-001 treatment of LD-MMI and HD-MMI increases oligodendrogenesis, myelin and axon density in the corpus callosum and striatal WM bundles, promotes WM integrity and attenuates neurological and cognitive deficits. Additionally, both LD-MMI and HD-MMI rats exhibit a significant increase, while AV-001 significantly decreases the levels of inflammatory factors in the cerebrospinal fluid (CSF).ConclusionMMI reduces oligodendrogenesis, and induces demyelination, axonal injury and WM injury, and causes memory impairment, while HD-MMI induces increased WM injury and further depression-like behaviors compared to LD-MMI rats. AV-001 has a therapeutic effect on aged female rats with MMI by reducing WM damage and improving neuro-cognitive outcomes.

Abstract Background Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used classes of medications, and are among the leading causes of drug hypersensitivity. NSAIDs hypersensitivity reactions are classified by symptom involvement and NSAIDs subclass cross-reactivity. Reactions varying from cutaneous involvement to respiratory symptoms can be triggered by multiple NSAIDs subclasses. Anaphylaxis, while rare, can be induced by a single NSAID, with tolerability of other structurally unrelated subclasses. Reactions that fall outside of these traditional categories are deemed “blended reactions”. We report a unique case of possible anaphylaxis to acetylsalicylic acid (ASA) and ibuprofen, two structurally dissimilar NSAIDs, indicating a severe blended reaction outside of the typical NSAIDs hypersensitivity reaction categories. Case presentation An otherwise healthy 45 year old woman was referred to the Allergy and Immunology clinic after developing acute onset dyspnea, lip swelling, and generalized urticaria with ibuprofen use requiring treatment with intramuscular epinephrine in the emergency department. She previously tolerated ibuprofen, naproxen, and acetaminophen and had no history of urticaria, angioedema, asthma, or nasal polyps. She underwent an oral challenge to ASA whereby she developed urticaria and throat irritation with rebound symptoms requiring 2 doses of intramuscular epinephrine. On subsequent visits she passed treatment dose acetaminophen and celecoxib challenges. She was counseled to avoid all other NSAIDs and ASA desensitization was offered should this medication be clinically indicated in the future. Conclusions NSAIDs hypersensitivity reactions can be triggered by individual NSAIDs with tolerance of other subclasses or by multiple structurally unrelated NSAIDs due to COX-1 inhibition. Determining the type of reaction (NERD, NECD, NIUA, SNIUAA, or SNIDHR) allows for appropriate oral challenges and safe alternative therapy recommendations. However, not all clinical reactions fit perfectly into these categories. Patients may also develop blended reactions. Our case highlights a severe blended reaction to multiple unrelated NSAIDs, including likely anaphylaxis to ASA. We note the utility of drug provocation tests (DPTs) to identify safe alternative medication options, as well as the importance of performing DPTs in settings properly equipped to assess and manage severe hypersensitivity reactions including anaphylaxis.

Abstract Background Hereditary angioedema (HAE) is a rare disease characterized by unpredictable, recurring subcutaneous or submucosal swelling. Without effective therapy, HAE can negatively impact patients’ quality of life. Management of HAE includes on-demand treatment of attacks and short- and long-term prophylaxis (LTP) to prevent attacks. Newer therapies may be more tolerable and effective in managing HAE; however, therapies such as androgens are still widely used in some countries owing to their relative ease of access and adequate disease control for some patients. This study evaluated the characteristics, treatment patterns, clinical outcomes, and healthcare resource utilization of a multinational cohort of patients with HAE, with a focus on understanding reasons for recommending or discontinuing available therapies. Methods A retrospective chart review was conducted at 12 centers in six countries and included data from patients with HAE type 1 or 2 who were ≥ 12 years of age at their first clinical visit. The relationship between LTP use and attack rates was evaluated using a multivariable Poisson regression model. Data were collected between March 2018 and July 2019. Results Data from 225 patients were collected (62.7% female, 86.2% White, 90.2% type 1); 64.4% of patients had their first HAE-related visit to the center prior to or during 2014. Treatment patterns varied between countries. Overall, 85.8% of patients were prescribed on-demand treatment and 53.8% were prescribed LTP, most commonly the androgen danazol (53.7% of patients who used LTP). Plasma-derived C1 inhibitor (Cinryze®) was used by 29.8% of patients for LTP. Patients who received LTP had a significantly lower rate of HAE attacks than patients who did not receive any LTP (incidence rate ratio (95% confidence interval) 0.90 (0.84–0.96)). Androgens were the most commonly discontinued therapy (51.3%), with low tolerability cited as the most frequent reason for discontinuation (50.0%). Conclusions Overall, findings from this study support the use of LTP in the prevention of HAE attacks; a lower rate of attacks was observed with LTP compared with no LTP. However, the type of LTP used varied between countries, with tolerability and accessibility to specific treatments playing important roles in management decision-making.

Abstract Background Chronic rhinosinusitis with nasal polyposis (CRSwNP) often coexists with lower airway disease. With the overlap between upper and lower airway disease, optimal management of the upper airways is undertaken in conjunction with that of the lower airways. Biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of both upper and lower airway diseases. Knowledge gaps nevertheless exist in how best to approach patient care as a whole. There have been sixteen randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL- 5R, IL-33, and immunoglobulin (Ig)E. This white paper considers the perspectives of experts in various disciplines such as rhinology, allergy, and respirology across Canada, all of whom have unique and valuable insights to contribute on how to best approach patients with upper airway disease from a multidisciplinary perspective. Methods A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. A national multidisciplinary expert panel of 34 certified specialists was created, composed of 16 rhinologists, 7 allergists, and 11 respirologists who evaluated the 20 original statements on a scale of 1–9 and provided comments. All ratings were quantitively reviewed by mean, median, mode, range, standard deviation and inter-rater reliability. Consensus was defined by relative interrater reliability measures—kappa coefficient ( $$\kappa$$ κ ) value > 0.61. Results After three rounds, a total of 22 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with upper airway disease. Conclusion This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of upper airway disease from a multidisciplinary perspective, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years. Graphical abstract

Abstract Background Oral food challenges (OFC) confer the highest sensitivity and specificity in diagnosis; however, uptake has been variable across clinical settings. Numerous barriers were identified in literature from inadequate training to resource access. OFC utilization patterns using billing data have not been previously studied. Objective The objective of this study is to explore the geographic differences in utilization of OFCs across Ontario and Québec using anonymized billing data from 2013 to 2017. Methods Anonymized OFC billing data were obtained between 2013 and 2017 from Ontario Health Insurance Plan (OHIP) and Régie de l'Assurance Maladie du Québec (RAMQ). The number of OFCs was extracted by location, billings, and physician demographics for clinic and hospital-based challenges. Results Over the period studied, the number of OFCs increased by 92% and 85% in Ontario clinics and Québec hospitals, respectively. For Ontario hospitals, the number of OFCs increased by 194%. While Québec performed exclusively hospital-based OFCs, after controlling for the population, the number of OFCs per 100,000 residents annually were similar to Ontario at 50 and 49 OFCs, respectively. The number of OFCs varied across the regions studied with an annual rate reaching up to 156 OFCs per 100,000 residents in urban regions and as low as 0.1 in regions furthest from city centers. Conclusion OFC utilization has steadily increased over the last decade. There has been marked geographical discrepancies in OFC utilization which could be driven by the location of allergists and heterogeneity in their practices. More research is needed to identify barriers and propose solutions to them.

Abstract Background In anaphylaxis, the dosing of injectable epinephrine in medical settings has been arbitrarily recommended to be 0.01 mg/kg of body weight. For ethical reasons, there have been no dose–response studies or double-blind studies performed on patients with active anaphylaxis. Intramuscular delivery of epinephrine has been the standard. Auto-injectors for use in the treatment of anaphylaxis are available in four strengths (0.1, 0.15, 0.3, and 0.5 mg). However, in many countries, only the 0.15 and 0.3 mg strengths are available. Consequently, many adult, heavy patients are prescribed the 0.3 mg dose, which may result in only one-fifth to one-third of the recommended weight-based dose being administered in heavy patients experiencing anaphylaxis. Underdosing may have therefore contributed to mortality in anaphylaxis. Objective To review the doses of epinephrine recommended for the treatment of anaphylaxis in the community, and assess whether recommendations should be made to increase dosing for heavy adult patients in hopes of avoiding future deaths from anaphylaxis. Methods We reviewed multiple national and international recommendations for the dosing of epinephrine. We also reviewed the literature on adverse drug reactions from epinephrine, lethal doses of epinephrine, and epinephrine dose-finding studies. Results The majority of national and regional professional societies and authorities recommend epinephrine delivered by auto-injectors at doses far lower than the generally accepted therapeutic dose of 0.01 mg/kg body weight. Furthermore, we found that the recommendations vary even within regions themselves. Conclusions We suggest prescribing more appropriate doses of epinephrine auto-injectors based on weight-based recommendations. There may be some exceptions, such as for patients with heart disease. We hypothesize that these recommendations will lead to improved outcomes of anaphylaxis.

Abstract Background Real-world data on transitioning to Immune Globulin Subcutaneous (Human) 20% solution (Ig20Gly) are limited. This study aimed to assess infusion parameters and experience of patients with primary (PID) or secondary immunodeficiencies (SID) transitioning to Ig20Gly in clinical practice in Canada. Methods Patients with PID or SID who received subcutaneous immunoglobulin (SCIG) for ≥ 3 months before transitioning to Ig20Gly were eligible for this multicenter (n = 6), phase 4, non-interventional, prospective, single-arm study. Ig20Gly infusion parameters, dosing, and adverse events were collected from patient medical records at Ig20Gly initiation and 3, 6, and 12 months post-initiation. Patient satisfaction and quality of life were assessed 12 months post-initiation using validated questionnaires. Results The study included 125 patients (PID, n = 60; SID, n = 64; PID + SID, n = 1). Median volume per infusion was 30.0 ml at initiation, and 40.0 ml at 6 and 12 months post-initiation. Most patients administered Ig20Gly weekly and used two infusion sites (primarily abdomen). At each time point, median infusion duration was ≤ 1 h. At 12 months, 61% of infusions were administered via a pump and 39% manually. Headache and infusion-site reactions were the most reported adverse events of interest. Patients expressed overall satisfaction with Ig20Gly at 12 months post-initiation, with all respondents indicating they would like to continue Ig20Gly. Conclusions This study provides a detailed description of Ig20Gly infusion parameters, tolerability, and quality of life in clinical practice among patients with PID or SID switching to Ig20Gly from another SCIG and confirms the feasibility of infusing Ig20Gly via pump or manual administration. Trial registration NCT03716700, Registered 31 August 2018, https://clinicaltrials.gov/ct2/show/NCT03716700

Background: The safety of pediatric food oral immunotherapy (Ped-OIT) has been depicted by some as less favorable than subcutaneous immunotherapy (SCIT) owing to the increased number of serious adverse events requiring epinephrine. A review of real-world data comparing Ped-OIT and SCIT safety is necessary to guide shared decision making. Objectives: Our aim was to compare the safety and adverse event profiles of peanut Ped-OIT and SCIT using Canadian real-word literature. Methods: We performed a retrospective review of recent Canadian real-world literature on peanut Ped-OIT and SCIT safety and adverse events. Results: The incidences of systemic reactions requiring epinephrine were 11 in 270 patients (4.07%) and 12 in 41,020 doses (0.029%) in a multicenter study in British Columbia, Alberta, Manitoba, and Nova Scotia studying 270 preschool-age children treated with peanut OIT. Similarly, a multicenter study in South-Western Ontario examining 160 patients between the ages of 1 and 17 years who were treated with peanut OIT showed that the incidences of systemic reactions requiring epinephrine were 5 in 160 patients (3.1%) and 8 in 52,751 doses (0.015%). A single-center retrospective review of 380 patients receiving aeroallergen SCIT showed that the incidences of systemic reactions requiring epinephrine were 28 in 380 patients (7.4%) and 1 in 1047 injection visits (0.095%). These findings are comparable to those of a review of 860 patients in Ontario who received either aeroallergen or venom SCIT, in which the incidence of systemic reaction requiring epinephrine was 10 in 4242 injections (0.24%). Conclusion: Despite differences in the OIT protocols used and age groups studied, recent real-world data suggest that the safety of preschool peanut OIT or peanut OIT using a slower buildup schedule is comparable to that of SCIT.

Abstract Background In the era of COVID-19, utilization of telemedicine has dramatically increased. In addition to reduced travel times, patient expenses, and work or school days missed, telemedicine allows clinicians to provide continued care while minimizing face-to-face interactions, maintaining social distancing, and limiting potential COVID-19 exposures. Clinical Immunology and Allergy (CIA), like many specialties, has adapted to incorporate telemedicine into practice. Previous studies have demonstrated similar patient satisfaction between virtual and in-person visits. However, evidence from fully publicly funded health care systems such as Canada has been limited. Methods We performed a quality improvement (QI) initiative to assess the feasibility of telemedicine. Between 1 March and 30 September 2020, patient encounters of two academic allergists at a single institution in London, Ontario, Canada were analyzed. Assessments were categorized into in-person or telemedicine appointments. A random sample of patients assessed virtually completed a voluntary patient satisfaction survey. Qualitative analysis was performed on survey comments. Results In total 3342 patients were seen. The majority were adults (n = 2162, or 64.7%) and female (n = 1872, or 56%). 1543 (46.2%) assessments were virtual and 1799 (53.8%) assessments were in-person. 67 of 100 random patient surveys sent to those in the virtual assessment group were completed. 89.6% (n = 60) agreed or strongly agreed when asked if they were satisfied with their telemedicine visit. 64.2% (n = 43) felt they received the same level of care compared to in-person assessments and 91% (n = 61) stated they would attend another virtual appointment. 95.4% (n = 62) of patients reported saving time with virtual assessment, the majority (n = 42, 62.7%) estimating between 1–4 h saved. Reported shortcomings included technical difficulties, “feeling rushed”, and missing in-person interactions. Conclusions Our quality improvement initiative demonstrated high patient satisfaction and time savings with virtual assessment in a publicly funded health care system. Studies suggest that CIA may be uniquely situated to benefit from permanent integration of virtual care into regular practice for both new and follow-up appointments. We anticipate continued increased utilization of telemedicine, signifying a lasting beneficial change in the delivery of healthcare.

Abstract Background Food Protein-Induced Enterocolitis Syndrome (FPIES) is a non-IgE mediated food allergy most commonly presenting in infants. The most common food triggers include soy, cow’s milk and grains. Symptoms may include intractable vomiting, diarrhea, lethargy, pallor, abdominal distention, hypotension and/or shock. Oral food challenges (OFCs) given at food protein dose of 0.06–0.6 g/kg in 3 equivalent doses administered over a few hours are recommended in guidelines to confirm a diagnosis. Case presentation The patient is a 6-month-old girl with a history of severe FPIES symptoms to egg. In our clinic, we perform OFC with 1/100 serving dose on visit 1 and then increase the dose monthly. The patient takes the tolerated dose daily at home between visits. An OFC to baked egg at 1/100 of a serving was performed and was well-tolerated on her initial visit. The patient remained on the same dose upon returning home. Within 1-week, she developed FPIES symptoms including watery diarrhea and severe emesis requiring ondansetron. She required an Emergency Department visit for one of the reactions. Conclusions Our patient had severe FPIES symptoms with a small amount of egg. We believe that administration of three large food challenge doses on one clinic visit, as guidelines currently suggest, does not allow adequate time for symptoms to appear. Our patient likely would have suffered a severe reaction. Also, this guidelines protocol does not allow for monitoring of more delayed or chronic FPIES. We propose a modified protocol to OFCs with cautious up-dosing to allow for safer OFCs and monitoring of chronic FPIES. We have implemented an OFC approach where only one food challenge dose (starting with 1/100 of final dose) is given at each visit. The up-titration of the dose is completed every 4-weeks with one dose only. When the serving sized dose is reached and tolerated, the food can be maintained in the diet.

Abstract Owing to a collaborative approach to patient care, and a paucity of allergists in Canada, there is a need to develop a food allergy educational program for allied health care professionals in Canada. Such programs already exist in the United States and Britain. Herein, we describe the outcomes of recent conference proceedings to inform the educational needs for such a program. As part of the 76th Annual Meeting of the Canadian Society of Allergy and Clinical Immunology (CSACI), held virtually due to the COVID-19 pandemic, we hosted a virtual workshop on the need for a food allergy educator program for Canadian allied health professionals. This workshop was co-developed with the CSACI and an industry partner, and featured allergy specialist dietitians. Attendance was open to all conference delegates, and to allied health professionals. As part of the registration process, registrants posed diverse food allergy-related questions, ranging from how to use an epinephrine autoinjector, to daily management and, how to cure food allergy. A national food allergy educator program will empower both allergy and non-allergy specialist healthcare professionals to appropriately counsel patients. This virtually-delivered program will begin to close a gap in healthcare access resulting from the geographic size of Canada, as it will enhance allied healthcare providers’ confidence to provide evidence-based food allergy care appropriately for those with food allergy.

Abstract Background Allergen extracts used in subcutaneous immunotherapy can be standardized or non-standardized. Standardized extracts are available in specific biological potencies, presumably making their biological activity more consistent. The majority of allergen extracts are non-standardized and may have less consistent potencies. Non-standardized extracts are labeled as weight per volume or protein nitrogen units (PNUs). Neither method provides direct information regarding the extract’s biologic potency. The purpose of this study was to compare weight per volume versus PNU concentrations for 4 non-standardized allergen extracts prepared by two allergen manufacturers. The potencies were compared to current North American practice recommendations. Methods The weight per volume and PNU values were provided for 4 non-standardized extracts—birch, short ragweed, dog hair and Alternaria—from HollisterStier and Stallergenes Greer. Weight per volume and PNU concentrations were compared for each of these extracts from both manufacturers. From the raw data, we calculated the corresponding PNU values for a weight per volume of 1:100 and 1:200 for each extract. Similarly, we calculated the corresponding weight per volume including a range of PNU values, for 1000, 2000, 3000, 4000 and 5000 PNU/ml. Results Birch extract has low PNU concentration, below 5000, for a weight per volume of 1:200 for both HollisterStier and Stallergenes Greer. In contrast, for both HollisterStier and Stallergenes Greer ragweed extract, a weight per volume of 1:200 corresponds to a PNU concentration greater than 5000. Dog extract for a weight per volume of 1:200, and even for 1:100, corresponds to very low PNUs for both companies. For Alternaria, corresponding PNU concentrations for HollisterStier is low at only 500 while over 5000 for Stallergenes Greer. Conclusions Our results show variability when comparing weight per volume and PNU concentrations for both Hollister-Stier and Stallergenes Greer products. We suggest selecting a PNU dose that corresponds to a weight per volume of 1:200 as this may improve patient safety. Our recommendations for starting PNU dose for the four non-standardized extracts are 1500 for birch, 5000 for ragweed, 25 for dog, and 500 for Alternaria when using HollisterStier products; 2300 for birch, 5000 for ragweed, 1200 for dog, and 5000 for Alternaria when using Stallergenes Greer products. If the starting PNU concentration is considerably below 5000 for a weight per volume of 1:200 slow up-titration is advised. Conversely, for PNU concentrations above 5000 for weight per volume of 1:200 we suggest a maintenance dose of 5000 PNU.

Abstract Background Subcutaneous immunotherapy (SCIT) is an effective treatment for allergic rhinoconjunctivitis. However, adverse events, including life-threatening systemic reactions, may occur. The purpose of this project is to identify risk factors for systemic reactions to SCIT and to provide practice-based solutions using a quality improvement (QI) framework. Methods A QI initiative was performed in a hospital-based, Canadian Allergy clinic administering SCIT in a 12-month period. Results A total of 4242 injections of SCIT were performed over a period of 12 months. Of these, 10 injections resulted in a systemic reaction requiring epinephrine administration (i.e., an incidence of 1 in 424 injections, or 0.24%). Eight patients had at least one documented risk factor for a systemic reaction, and six had multiple risk factors. Major risk factors included seasonal exacerbation of allergic rhinitis, uncontrolled asthma, and an error in route of administration. All reactions occurred with the highest allergen extract concentration. Conclusion This QI initiative highlights the need for improved patient and health care practitioner education and pre-administration screening. We suggest several considerations for SCIT administration: provide patients with written information on safety; screen patients before injections, including a review of treatment plan adherence and asthma control; adjust dosing to slow down buildup of the most concentrated immunotherapy extract, particularly in high risk patients; and apply additional safety measures in patients with multiple risk factors.

Abstract Background Autoimmune progesterone dermatitis (APD) is a rare skin condition caused by sensitivity to high levels of progesterone secreted during the luteal phase of the menstrual cycle. This may be due to various pathophysiological mechanisms including a Type I and Type IV hypersensitivity reaction. Here we present the case of a patient with APD whose episodic flares were controlled by the addition of omalizumab, after a bilateral oophorectomy failed to resolve her symptoms. Case Presentation A 34-year-old female presented to our Endocrine clinic with marked Cushingoid features secondary to high-dose oral prednisone prescribed for APD diagnosed 6 years earlier. She first developed a pruritic maculopapular rash on her arms and legs just after the birth of her second child in 2009. The rash was also associated with headaches and diffuse angioedema. Symptoms occurred for 1–2 weeks, in a cyclical fashion, during the luteal phase of each menstrual cycle and subsided within a few days after menses. The severity of symptoms increased as time went on, and flare-ups began to also include dyspnea, nausea, vomiting and abdominal pain. Her symptoms improved with administration of oral prednisone, but she continued to experience breakthrough symptoms. After multiple failed treatment modalities, she elected bilateral oophorectomy in 2018. However, her symptoms of APD persisted and she still required high-dose oral prednisone. Her condition was further complicated by vasomotor menopausal symptoms and progressive iatrogenic Cushing’s syndrome. She eventually was started on Omalizumab, which suppressed further recurrences of APD symptoms and allowed her to wean off prednisone. Vasomotor menopausal symptoms responded well to the addition of conjugated estrogens with bazedoxifene. However, her symptoms of diffuse bony pain and arthralgias which started whilst on prednisone have persisted in spite of discontinuing prednisone. Conclusions To our knowledge, this is only the third case of APD which was successfully treated with Omalizumab and the first case where a bilateral oophorectomy failed to resolve symptoms of APD in the literature. This case also demonstrates the complications of vasomotor menopausal symptoms secondary to a bilateral oophorectomy, as well as the adverse effects of long-term glucocorticoid therapy.

BackgroundThe COVID-19 pandemic has affected the supply, cost, and demand for certain foods, but it is not clear how these changes have affected food-allergic households.ObjectiveTo describe the changes in food-related costs that have followed COVID-19, as reported by higher- and lower-income households with a food-allergic member.MethodsBetween May 1-June 30, 2020, Canadian households, with at least one food-allergic member, completed an online survey on food shopping and preparation habits before and during the COVID-19 pandemic. The sample was divided into binary groups, either higher or lower than the sample median income. Data were analyzed using descriptive statistics and multiple regression.ResultsThe sample was comprised of 102 participants (i.e., 51/ income group). The three most common food allergies amongst both groups were peanuts, tree nuts and milk. Since the start of the pandemic, both groups reported greater monthly direct grocery costs, although costs amongst the higher-income group were twice as high as the lower-income group ($212.86 vs. $98.89, respectively). Indirect food preparation costs were similarly elevated. Higher-income households with food procurement difficulties reported increased indirect shopping costs following the outbreak of COVID-19, whereas those without such difficulties reported decreased costs. Lower-income households with allergies to milk, wheat, or eggs (i.e., staple allergy) experienced a larger change in indirect food preparation costs following the outbreak of COVID-19 relative to those with other food allergies ($244.58 vs. –$20.28, respectively; p = 0.03).ConclusionBoth higher and lower income households with food allergy reported greater direct food costs and indirect food preparation costs following the COVID-19. Households with staple allergy and those with difficulties finding their typical food items were particularly affected.

Abstract Background For a century, epinephrine has been the drug of choice for acute treatment of systemic allergic reactions/anaphylaxis. For 40 years, autoinjectors have been used for the treatment of anaphylaxis. Over the last 20 years, intramuscular epinephrine injected into the thigh has been recommended for optimal effect. Objective To review the literature on pharmacokinetics of epinephrine autoinjectors. Results Six studies assessing epinephrine autoinjector pharmacokinetics were identified. The studies, all on healthy volunteers, were completed by Simons, Edwards, Duvauchelle, Worm and Turner over the span of 2 decades. Simons et al. published two small studies that suggested that intramuscular injection was superior to subcutaneous injection. These findings were partially supported by Duvauchelle. Duvauchelle showed a proportional increase in Cmax and AUC0-20 when increasing the dose from 0.3 to 0.5 mg epinephrine intramuscularly. Turner confirmed these findings. Simons, Edwards and Duvauchelle documented the impact of epinephrine on heart rate and blood pressure. Turner confirmed a dose-dependent increase in heart rate, cardiac output and stroke volume. Based on limited data, confirmed intramuscular injections appeared to lead to faster Cmax. Two discernable Cmax’s were identified in most of the studies. We identified similarities and discrepancies in a number of variables in the aforementioned studies. Conclusions Intramuscular injection with higher doses of epinephrine appears to lead to a higher Cmax. There is a dose dependent increase in plasma concentration and AUC0-20. Most investigators found two Cmax’s with Tmax 5–10 min and 30–50 min, respectively. There is a need for conclusive trials to evaluate the differences between intramuscular and subcutaneous injections with the epinephrine delivery site confirmed with ultrasound.

Abstract Background Mepolizumab and benralizumab are biologics approved for severe eosinophilic asthma. Mepolizumab is an anti-interlukin-5 (IL-5) antibody while benralizumab is an anti-interleukin-5 receptor alpha (IL-5Rα) antibody targeting the IL-5 receptor on eosinophils. Both therapies reduce oral corticosteroid requirements and asthma exacerbations. However, no head-to-head studies have been published. The aim of the present study was to compare the efficacy of peripheral eosinophil reduction of mepolizumab and benralizumab. Methods A retrospective chart review was conducted on patients with severe eosinophilic asthma who were approved for either IL-5 agent. Patients with noted non-adherence or those who were on fluctuating doses of corticosteroids for non-asthma related illnesses were excluded. The last detectable eosinophil count for each patient prior to start of therapy was compared to the highest eosinophil count noted after therapy start with at least 30 days of adherence. Results Thirty-six patients taking mepolizumab and 19 patients taking benralizumab met the inclusion criteria and had both pre-treatment and post-treatment eosinophil counts. Baseline characteristics were not statistically different between those on mepolizumab and benralizumab therapy. The mean pre-therapy serum eosinophil count did not statistically differ between patients on mepolizumab (597.2 cells/µL) compared to benralizumab (521.6 cells/µL), p = 0.3769. While both therapies resulted in a significant decrease in eosinophil count (p

Abstract Background Food protein-induced enterocolitis (FPIES), an entity previously thought to only affect children, has been increasingly described in adults. In this study, we report a Canadian cohort of 19 adolescents and adults with recurrent non-immunoglobulin E (IgE)-mediated gastrointestinal symptoms after crustacean ingestion, consistent with FPIES. Methods We conducted a retrospective chart review of patients in an outpatient allergy clinic from January 2005 to May 2020. Electronic records were searched using keywords for crustaceans and for symptoms consistent with FPIES. We included patients with gastrointestinal symptoms specifically to crustaceans on more than one occasion, who were 14 years or older at the time of index reaction. Exclusion criteria included symptoms suggestive of an IgE-mediated anaphylactic reaction or a likely alternative diagnosis. We identified 19 patients for our cohort who met the criteria. Results Our cohort was 68.4% female (13) and 32.6% (6) male. The average age at first reaction to crustaceans was 34 years old with a range of 14–68 years (median = 28 years; IQR = 32 years). Time from ingestion to beginning of symptoms ranged from 3 min to 6.5 h, with an average of 2.8 h (median = 2 h; IQR = 3.25 h). Duration of reaction ranged from less than a minute to over 48 h, with a mean of 9.4 h (median = 4 h; IQR = 7.75 h). Patients had 4.8 reactions on average; however, number of reactions ranged from 2 to 12.5 (median = 3, IQR = 3). All patients identified a “trigger” food in the crustacean group, and 12 subjects identified additional reactions to other seafood. Conclusions This case series will better characterize and advance our understanding of this disease entity in adults. There are key differences in the presentation of FPIES in adults compared to children, namely female predominance, difference in solid food trigger, and unpredictable time course. Future studies are needed to examine the pathophysiology and natural history of adult FPIES. Specific guidelines should be developed for the diagnosis and management in adults. Trial registration: retrospectively registered.

Abstract Background Subcutaneous immunotherapy (SCIT) is the standard approach for treating patients with sensitizations to aeroallergens. However, immunotherapy can trigger severe systemic reactions if delivered inappropriately or to high risk patients. We sought to characterize and quantify SCIT systemic reactions requiring epinephrine administration during a 6-year period in a Canadian setting following the recommendations for components and dosages published in the 2010 Canadian Society of Allergy and Clinical Immunology (CSACI) Immunotherapy Manual. Methods A single centre retrospective chart review was performed for all patients with systemic reactions to subcutaneous immunotherapy requiring intramuscular epinephrine injection between January 2011 and October 2017. Each systemic reaction requiring epinephrine was reviewed for baseline patient characteristics, details of the reaction, and reaction severity. Research ethics approval was obtained through McMaster University. Results 28 of 380 patients experienced a systemic reaction requiring epinephrine administration, with an incidence rate of 1 per 1,047 injection visits (0.095%). 26 of the 28 reactions occurred within the mandatory 30-minute observation period post allergen immunotherapy. Of the 28 patients that experienced a systemic reaction to SCIT, 11 patients had asthma and 5 patients had a history of possible food allergy. All of the systemic reactions occurred during injections from vial number 4, and five patients reacted to their first shot of a re-ordered extract. 10 of the 28 patients required more than one intramuscular injection of epinephrine, and 20 of 28 patients were transferred to the hospital by ambulance. Conclusions This is the first Canadian study to review patients with systemic reactions to subcutaneous immunotherapy. Several best practice methods were employed throughout the study to optimize subcutaneous delivery of immunotherapy extract, and our recorded per injection incidence rate for systemic reactions was comparable or below the rate published in similar studies. The recommendations in the CSACI Immunotherapy Manual provide an approach to standardizing prescriptions for SCIT to maximize immunotherapy efficacy and reduce the risk of systemic reactions, though similar studies in larger multicenter settings are needed to confirm these observations. These observations provide important objective information to clinicians about the potential risks for systemic reactions in patients considering SCIT.

Abstract Background Epinephrine auto-injectors are expected to deliver the drug intramuscularly. Objective To study whether injection through clothing influences the frequency of subcutaneous and intraosseous/periosteal deposition of epinephrine. Methods Skin to muscle and skin to bone distances were measured for 303 children and adolescents and 99 adults. Distance was determined by ultrasound, with high or low pressure on the ultrasound probe. The risk/percentage of subcutaneous and intraosseous/periosteal injections was calculated using the lower and upper limits for the authority-approved length of EAI needles as provided by two high pressure EAI manufacturers and one low pressure EAI manufacturer. The addition winter clothing on the delivery of epinephrine was illustrated by comparing drug delivery fissue depth with no clothes. Furthermore, the riof non-intramuscular delivery for the shortest and longest approved needle length was calculated. Results When using EpipenJr® in children

Abstract Allergic eye disease is common, yet often overlooked in North America. In the U.S., up to 40% of the population is deemed to be affected and this number is growing. Symptoms and signs of ocular allergy can lead to decreased productivity and negatively impact quality of life (QoL). Various treatment options exist to achieve symptom control. For allergic conjunctivitis, ophthalmic agents include antihistamines, mast cell stabilizers, dual-activity agents, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids and some off-label treatments. Immunotherapy is recommended as a therapeutic option. This review provides a summary of the forms of ocular allergies, with a focus on symptoms and signs, impact on QoL, physical examination, diagnosis and therapeutic options of allergic conjunctivitis. Through multidisciplinary collaborations, a simplified algorithm for the treatment of allergic conjunctivitis is proposed for Canadian clinical practice.

Abstract This is an update to the 2014 Canadian Hereditary Angioedema Guideline with an expanded scope to include the management of hereditary angioedema (HAE) patients worldwide. It is a collaboration of Canadian and international HAE experts and patient groups led by the Canadian Hereditary Angioedema Network. The objective of this guideline is to provide evidence-based recommendations, using the GRADE system, for the management of patients with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. New to the 2019 version of this guideline are sections covering the diagnosis and recommended therapies for acute treatment in HAE patients with normal C1-INH, as well as sections on pregnant and paediatric patients, patient associations and an HAE registry. Hereditary angioedema results in random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased health-related quality of life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada, as in many countries, continues to be neither optimal nor uniform. It lags behind some other countries where there are more organized models for HAE management, and greater availability of additional licensed therapeutic options. It is anticipated that providing this guideline to caregivers, policy makers, patients, and advocates will not only optimize the management of HAE, but also promote the importance of individualized care. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency and intensive care physicians, primary care physicians, gastroenterologists, dentists, otolaryngologists, paediatricians, and gynaecologists who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.

Abstract Background Based on immunologic phenotypes underlying asthma, use of monoclonal antibody based therapies is becoming the new standard of care for severe, corticosteroid refractory clinical symptoms. Patients may qualify for one or more of these targeted treatments, based on clinical characteristics and approved indications. However, the statistics are not well characterized, particularly in the Canadian population. Methods The objective of this observational study was to identify and describe the proportion of patients with severe asthma who were eligible for targeting IgE, IL-5, or both pathways of immunomodulation. We reviewed a cross-sectional cohort of patients in a Canadian Allergy and Immunology referral practice. We also compared demographic and clinical characteristics of each group. Results Of the 128 patients with severe asthma, 84 (66%) were eligible for omalizumab, 100 (78%) for mepolizumab, 52 (41%) for reslizumab, and 68 (53%) for benralizumab. Overlap in treatment eligibility varied; 68 (53%) patients were eligible for both omalizumab and mepolizumab, 47 (37%) were eligible for omalizumab and benralizumab, and 37 (29%) were eligible for all four medications. Patient demographics and clinical characteristics were similar, and levels of serum biomarkers varied based on locally approved prescribing criteria. Conclusion In this severe asthma population from a Canadian Allergist’s practice, one-third of individuals qualified for all currently available biologics. 41–78% were eligible for at least one mAb. Patients were most likely to be eligible for mepolizumab. Objective assessments to determine asthma phenotype, along with further characterization of safety profiles will lead to further advances in asthma management.

Abstract Allergic rhinitis is a common disorder that is strongly linked to asthma and conjunctivitis. It is usually a long-standing condition that often goes undetected in the primary-care setting. The classic symptoms of the disorder are nasal congestion, nasal itch, rhinorrhea and sneezing. A thorough history, physical examination and allergen skin testing are important for establishing the diagnosis of allergic rhinitis. Second-generation oral antihistamines and intranasal corticosteroids are the mainstay of treatment. Allergen immunotherapy is an effective immune-modulating treatment that should be recommended if pharmacologic therapy for allergic rhinitis is not effective or is not tolerated, or if chosen by the patient. This article provides an overview of the pathophysiology, diagnosis, and appropriate management of this disorder.

Abstract Allergen-specific immunotherapy is a potentially disease-modifying therapy that is effective for the treatment of allergic rhinitis/conjunctivitis, allergic asthma and stinging insect hypersensitivity. However, despite its proven efficacy in these conditions, it is frequently underutilized in Canada. The decision to proceed with allergen-specific immunotherapy should be made on a case-by-case basis, taking into account individual patient factors, such as the degree to which symptoms can be reduced by avoidance measures and pharmacological therapy, the amount and type of medication required to control symptoms, the adverse effects of pharmacological treatment, and patient preferences. Since this form of therapy carries a risk of anaphylactic reactions, it should only be prescribed by physicians who are adequately trained in the treatment of allergic conditions. Furthermore, for subcutaneous therapy, injections must be given under medical supervision in clinics that are equipped to manage anaphylaxis. In this article, the authors review the indications and contraindications, patient selection criteria, and details regarding the administration, safety and efficacy of allergen-specific immunotherapy.

Abstract Non-immunoglobulin E (IgE)-mediated food hypersensitivity includes a spectrum of disorders that predominantly affect the gastrointestinal tract. This review will focus on the following more common non-IgE-mediated food hypersensitivity syndromes: food protein-induced enterocolitis syndrome (FPIES), allergic proctocolitis (AP), food protein-induced enteropathy (FPE) and celiac disease. FPIES, AP and FPE typically present in infancy and are most commonly triggered by cow’s milk protein or soy. The usual presenting features are profuse emesis and dehydration in FPIES; blood-streaked and mucousy stools in AP; and protracted diarrhea with malabsorption in FPE. Since there are no confirmatory noninvasive diagnostic tests for most of these disorders, the diagnosis is based on a convincing history and resolution of symptoms with food avoidance. The mainstay of management for FPIES, AP and FPE is avoidance of the suspected inciting food, with periodic oral food challenges to assess for resolution, which generally occurs in the first few years of life. Celiac disease is an immune-mediated injury caused by the ingestion of gluten that leads to villous atrophy in the small intestine in genetically susceptible individuals. Serologic tests and small intestinal biopsy are required to confirm the diagnosis of celiac disease, and management requires life-long adherence to a strict gluten-free diet.

Abstract Anaphylaxis is an acute, potentially fatal systemic allergic reaction with varied mechanisms and clinical presentations. Although prompt recognition and treatment of anaphylaxis are imperative, both patients and healthcare professionals often fail to recognize and diagnose early signs and symptoms of the condition. Clinical manifestations vary widely; however, the most common signs are cutaneous symptoms, including urticaria, angioedema, erythema and pruritus. Immediate intramuscular administration of epinephrine into the anterolateral thigh is first-line therapy, even if the diagnosis is uncertain. The mainstays of long-term management include specialist assessment, avoidance measures, and the provision of an epinephrine auto-injector and an individualized anaphylaxis action plan. This article provides an overview of the causes, clinical features, diagnosis and acute and long-term management of this serious allergic reaction.

Abstract Asthma is the most common respiratory disorder in Canada. Despite significant improvement in the diagnosis and management of this disorder, the majority of Canadians with asthma remain poorly controlled. In most patients, however, control can be achieved through the use of avoidance measures and appropriate pharmacological interventions. Inhaled corticosteroids (ICS) represent the standard of care for the majority of patients. Combination ICS/long-acting beta2-agonist inhalers are preferred for most adults who fail to achieve control with ICS therapy. Biologic therapies targeting immunoglobulin E or interleukin-5 are recent additions to the asthma treatment armamentarium and may be useful in select cases of difficult to control asthma. Allergen-specific immunotherapy represents a potentially disease-modifying therapy for many patients with asthma, but should only be prescribed by physicians with appropriate training in allergy. In addition to avoidance measures and pharmacotherapy, essential components of asthma management include: regular monitoring of asthma control using objective testing measures such as spirometry, whenever feasible; creation of written asthma action plans; assessing barriers to treatment and adherence to therapy; and reviewing inhaler device technique. This article provides a review of current literature and guidelines for the appropriate diagnosis and management of asthma in adults and children.

Abstract Background Skin-to-bone distance (STBD) in children prescribed a pediatric epinephrine auto-injector (EAI) for anaphylaxis is not commonly measured in practice. Recent evidence suggests that children with STBD less than the exposed needle length of available pediatric EAIs (dose: 0.15 mg, needle length: 12.7 mm) are at risk for unintentional injections to the bone during their use for an allergic emergency. Case presentation Described here is a case of a female child with multiple food allergies prescribed a pediatric EAI (0.15 mg EpiPen Jr®) who experienced an unintentional injection to her femur. The patient’s STBD at the recommended injection site (vastus lateralis) was shorter than the needle length of her prescribed EAI (12.7 mm) at the time of the injury (age: 7, height: 122 cm; weight: 25 kg), even though her weight was within the indication for this EAI (15–30 kg). The patient and her family were made aware of the risk of unintentional bone injection at the time the EAI was prescribed. Conclusions Some children, even those at an appropriate weight per the indication of available pediatric EAIs (0.15 mg), may be at risk for unintentional injections to the bone. The effects of an unintentional bone injection with an EAI can have lasting effects on a child, including pain. Healthcare providers who prescribe pediatric EAIs for any child should consider evaluating this risk, inform patients and parents of the risk, and take measures to potentially mitigate unintentional bone injections. For some children, an EAI with a shorter needle length may be a more appropriate choice of treatment for anaphylaxis.

Abstract Background Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality worldwide. Despite effective antimicrobial therapy, CAP can induce pulmonary endothelial hyperpermeability resulting in life-threatening lung failure due to an exaggerated host-pathogen interaction. Treatment of acute lung injury is mainly supportive because key elements of inflammation-induced barrier disruption remain undetermined. Angiopoietin-1 (Ang-1)-mediated Tie2 activation reduces, and the Ang-1 antagonist Ang-2 increases, inflammation and endothelial permeability in sepsis. Vasculotide (VT) is a polyethylene glycol-clustered Tie2-binding peptide that mimics the actions of Ang-1. The aim of our study was to experimentally test whether VT is capable of diminishing pneumonia-induced lung injury. Methods VT binding and phosphorylation of Tie2 were analyzed using tryptophan fluorescence spectroscopy and phospho-Tie-2 enzyme-linked immunosorbent assay. Human and murine lung endothelial cells were investigated by immunofluorescence staining and electric cell-substrate impedance sensing. Pulmonary hyperpermeability was quantified in VT-pretreated, isolated, perfused, and ventilated mouse lungs stimulated with the pneumococcal exotoxin pneumolysin (PLY). Furthermore, Streptococcus pneumoniae-infected mice were therapeutically treated with VT. Results VT showed dose-dependent binding and phosphorylation of Tie2. Pretreatment with VT protected lung endothelial cell monolayers from PLY-induced disruption. In isolated mouse lungs, VT decreased PLY-induced pulmonary permeability. Likewise, therapeutic treatment with VT of S. pneumoniae-infected mice significantly reduced pneumonia-induced hyperpermeability. However, effects by VT on the pulmonary or systemic inflammatory response were not observed. Conclusions VT promoted pulmonary endothelial stability and reduced lung permeability in different models of pneumococcal pneumonia. Thus, VT may provide a novel therapeutic perspective for reduction of permeability in pneumococcal pneumonia-induced lung injury.

Abstract The heterogeneous nature of asthma has been understood for decades, but the precise categorization of asthma has taken on new clinical importance in the era of specific biologic therapy. The simple categories of allergic and non-allergic asthma have given way to more precise phenotypes that hint at underlying biologic mechanisms of variable airflow limitation and airways inflammation. Understanding these mechanisms is of particular importance for the approximately 10% of patients with severe asthma. Biomarkers that aid in phenotyping allow physicians to “personalize” treatment with targeted biologic agents. Unfortunately, testing for these biomarkers is not routine in patients whose asthma is refractory to standard therapy. Scientific advances in the recognition of sensitive and specific biomarkers are steadily outpacing the clinical availability of reliable and non-invasive assessment methods designed for the prompt and specific diagnosis, classification, treatment, and monitoring of severe asthma patients. This article provides a practical overview of current biomarkers and testing methods for prompt, effective management of patients with severe asthma that is refractory to standard therapy.

An amendment to this paper has been published and can be accessed via the original article.

Quantitative profiling of mRNA expression is an important part of understanding the state of a cell. The technique of RNA Fluorescence In Situ Hybridization (FISH) involves targeting an RNA transcript with a set of 40 complementary fluorescently labeled DNA oligonucleotide probes. However, there are many circumstances such as transcripts shorter than 200 nt, splicing variations, or alternate initiation sites that create transcripts that would be indistinguishable to a set of multiple probes. To this end we adapted the standard FISH protocol to allow the use of a single probe with a single fluorophore to quantify the amount of transcripts inside budding yeast cells. In addition to allowing the quantification of short transcripts or short features of transcripts, this technique reduces the cost of performing FISH.

mRNA Fluorescence In Situ Hybridization (FISH) is a technique commonly used to profile the distribution of transcripts in cells. When combined with the common single molecule technique Fluorescence Resonance Energy Transfer (FRET), FISH can also be used to profile the co-expression of nearby sequences in the transcript to measure processes such as alternate initiation or splicing variation of the transcript. Unlike in a conventional FISH method using multiple probes to target a single transcript, FRET is limited to the use of two probes labeled with matched dyes and requires the use of sensitized emission. Any widefield microscope capable of sensitive single molecule detection of Cy3 and Cy5 should be able to measure FRET in yeast cells. Alternatively, a FRET-FISH method can be used to unambiguously ascertain identity of the transcript without the use of a guide probe set used in other FISH techniques.

Background Immunotherapy targeting the checkpoint PD1 (programmed cell death protein 1) or PDL1 (programmed death ligand 1) has led to advances in the treatment of melanoma and non-small cell lung cancer (NSCLC). The use of such therapies has also been introduced into the treatment of other malignancies, including head and neck cancer. The combined effects of checkpoint inhibitors and anti-PD1(L1) antibodies and radiation therapy have not yet been sufficiently investigated.Case presentation We report a case of locally relapsed non-resectable oral cavity squamous cell carcinoma, with excellent local control after pembrolizumab (MK3475) followed by radiotherapy.Conclusion T cell activation induced by checkpoint inhibition may dramatically improve tumor response to radiation. More data are needed to identify the toxicity and efficacy of sequential or concurrent checkpoint inhibitors and radiotherapy.

ObjectiveTo explore the association of a functional germline variant in the 3'-UTR of KRAS with endometrial cancer risk, as well as the association of microRNA (miRNA) signatures and the KRAS-variant with clinical characteristics and survival outcomes in two prospective RTOG endometrial cancer trials.Methods/materialsThe association of the KRAS-variant with endometrial cancer risk was evaluated by case-control analysis of 467 women with type 1 or 2 endometrial cancer and 582 age-matched controls. miRNA and DNA were isolated for expression profiling and genotyping from tumor specimens of 46 women with type 1 endometrial cancer enrolled in RTOG trials 9708 and 9905. miRNA expression levels and KRAS-variant genotype were correlated with patient and tumor characteristics, and survival outcomes were evaluated by variant allele type.ResultsThe KRAS-variant was not significantly associated with overall endometrial cancer risk (14% controls and 17% type 1 cancers), although was enriched in type 2 endometrial cancers (24%, p = 0.2). In the combined analysis of RTOG 9708/9905, miRNA expression differed by age, presence of lymphovascular invasion and KRAS-variant status. Overall survival rates at 3 years for patients with the variant and wild-type alleles were 100% and 77% (HR 0.3, p = 0.24), respectively, favoring the variant.ConclusionsThe KRAS-variant may be a genetic marker of risk for type 2 endometrial cancers. In addition, tumor miRNA expression appears to be associated with patient age, lymphovascular invasion and the KRAS-variant, supporting the hypothesis that altered tumor biology can be measured by miRNA expression, and that the KRAS-variant likely impacts endometrial tumor biology.

Lymphangiogenesis is a highly regulated process that involves the reprogramming of venous endothelial cells into early lymphatic endothelial cells. This reprogramming not only displays a polarized expression pattern from the cardinal vein, but also demonstrates vascular specificity; early lymphatics only develop from the cardinal vein and not the related dorsal aorta. In our transgenic model of lymphangiogenesis, we demonstrate that Prox1 overexpression has the ability to reprogram venous endothelium but not early arterial endothelial cells in vivo, in spite of the fact that Prox1 expression is forced onto both vascular beds. Our observations suggest that this specificity during embryogenesis may be due to cell-cell interactions between the developing arterial endothelial cells and smooth muscle cells. These conclusions have far reaching implications on how we understand the vascular specificity of lymphangiogenesis.

Head and neck sarcomas are relatively rare tumors, with angiosarcomas representing a small subset. Angiosarcoma is a malignant endothelial neoplasm characterized by atypical, multilayered, or solid endothelial proliferation with vasoformative architecture. The global incidence of irradiation-associated sarcoma is estimated as between 0.03% and 0.08%. Here we reported the case of an elderly woman previously treated with radiation more than 20 years ago for an unknown primary of head and neck. This interesting case presented as a diagnostic challenge, and multiple biopsies were required to eventually establish the diagnosis of laryngeal angiosarcoma. We additionally have confirmation from our prior radiation records that the patient did, in fact, receive a substantial dose of radiation to the site previously. To our knowledge, this case represents the first report of a documented radiation-induced multifocal laryngeal angiosarcoma.

Most asthma patients prescribed maintenance asthma therapies still experience periods of asthma worsenings characterized by daytime or nighttime symptoms, or an increased need for rescue medication. In fact, these episodes are highly prevalent even in patients with well-controlled disease. Published literature suggests that asthma worsenings likely represent a window of opportunity during which patients could intervene early to prevent exacerbations or further deterioration of asthma symptoms. However, current evidence suggests that most patients fail to respond or to self-manage appropriately during these periods.

BACKGROUND: Several sets of Canadian guidelines for the diagnosis and management of asthma have been published over the past 15 years. Since the last revision of the 1999 Canadian Asthma Consensus Report, important new studies have highlighted the need to incorporate new information into the asthma guidelines.