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Multiple myeloma (MM) is an incurable plasma cell malignancy. In the context of the current standard of care therapies in Canada, outcomes among patients with relapsed/refractory multiple myeloma (RRMM), particularly those with triple-class (or more) refractory disease remain poor. Immunotherapies have significantly changed the treatment landscape of MM. Since 2021, two BCMA-targeting CAR T-cell therapy products have been approved for RRMM—namely Idecabtagene vicleucel (Ide-cel) (ABECMA®) and Ciltacabtagene autoleucel (Cilta-cel) (CARVYKTI®), both of which are available in the US and Europe. Although they have shown unprecedented efficacy in RRMM, their clinical and logistical limitations must be acknowledged. MM CAR T-cell therapy is likely to be approved in Canada soon. Therefore, it is timely that we review the latest evidence for commercially available CAR T-cell therapy in multiple myeloma, with a focus on its relevance and impact in the Canadian setting. There will be challenges to access and strategies must be in place to ensure equitable care for all Canadians with MM. Alongside haematologists working in the immune effector cell therapy programs, providers in the community will also play a role in the ongoing monitoring and management of long-term side effects including opportunistic infections and late neurotoxicity. [ABSTRACT FROM AUTHOR]

This epidemiological model forecasted reductions in recurrences and recurrence treatment cost savings with adjuvant atezolizumab vs best supportive care among Canadians with stage II-IIIA non-small cell lung cancer (NSCLC) at national and provincial levels. The population had resected, programmed cell death 1 ligand 1 (PD-L1)–high (≥50%), EGFR−, ALK−, stage II-IIIA NSCLC eligible for adjuvant treatment. Patients with recurrence or death and the costs of treating recurrences were estimated for those receiving adjuvant atezolizumab or best supportive care each year (2024–2034). Proportions of patients expected to be event free up to 10 years after treatment initiation were extrapolated with parametric survival analyses. In the base case analysis, 240 fewer recurrences were estimated to occur over 10 years (2024–2034) with adjuvant atezolizumab vs best supportive care across Canada, with 136 (57%) and 104 (43%) fewer locoregional and metastatic recurrences, respectively. Projected costs of treated recurrences were CAD 33.2 million less over 10 years with adjuvant atezolizumab at a national level (adjuvant atezolizumab, CAD 135.8 million; best supportive care, CAD 169.0 million). This model predicts a considerable long-term reduction in recurrences and substantial treatment cost savings with adjuvant atezolizumab vs best supportive care for patients with PD-L1–high early-stage NSCLC in Canada. [ABSTRACT FROM AUTHOR]

Locally advanced or metastatic urothelial carcinoma (aUC) presents a significant challenge with high mortality rates. Platinum-based chemotherapy remains the established frontline standard of care, and a switch-maintenance strategy with immunotherapy has now emerged as a new standard for aUC patients without disease progression, following initial platinum therapy. Examining the treatment patterns is imperative, given the evolving therapeutic landscape. In this study, we conducted a retrospective medical chart review of 17 Canadian oncologists treating patients with aUC to assess unmet needs in Canadian aUC patient care. Data from 146 patient charts were analyzed, revealing important clinical insights about the management of aUC. A substantial proportion of patients (53%) presented with de novo metastatic disease, which was possibly influenced by pandemic-related care disruptions. Variability was evident in the cisplatin eligibility criteria, with a majority (70%) of oncologists utilizing a 50 mL/min threshold. Most favored four cycles of platinum-based chemotherapy to spare the bone marrow for future therapies and prevent patient fatigue. Notably, some eligible patients were kept under surveillance rather than receiving maintenance therapy, suggesting a potential gap in awareness regarding evidence-based recommendations. Furthermore, managing treatment-related adverse events was found to be one of the biggest challenges in relation to maintenance immunotherapy. In conclusion, our findings provide the first comprehensive overview of aUC treatment patterns in Canada following the approval of maintenance immunotherapy, offering insights into the decision-making process and underscoring the importance of evidence-based guidelines in aUC patient management. [ABSTRACT FROM AUTHOR]

Background: The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to "out‐of‐trial" use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020. Methods: Innovative therapies were defined as cancer‐directed drugs used (a) off‐label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics. We excluded cytotoxic chemotherapy, cellular products, and cytokines. Results: We retrieved data on 352 innovative therapy drug requests. Underlying diagnosis was primary CNS tumor 31%; extracranial solid tumor 37%, leukemia/lymphoma 22%, LCH 2%, and plexiform neurofibroma 6%. RAS/MAP kinase pathway inhibitors were the most frequently requested innovative therapies in 28% of all requests followed by multi‐targeted tyrosine kinase inhibitors (17%), inhibitors of the PIK3CA‐mTOR‐AKT pathway (8%), immune checkpoints inhibitors (8%), and antibody drug conjugates (8%). In 112 out of 352 requests, innovative therapies were used in combination with another anticancer agent. 48% of requests were motivated by the presence of an actionable molecular target. Compassionate access accounted for 52% of all requests while public insurance was used in 27%. Mechanisms of funding varied between provinces. Conclusion: This real‐world data collection illustrates an increasing use of "out‐of‐trial" innovative therapies in pediatric oncology. This new field of practice warrants further studies to understand the impact on patient trajectory and equity in access to innovative therapies. [ABSTRACT FROM AUTHOR]

Immunotherapy (IO) with or without targeted therapy (TT) is the standard treatment for patients with metastatic clear cell renal cell carcinoma (RCC). The evidence supporting their use in metastatic nonclear cell renal cell carcinoma (nccRCC) subtypes is based on small prospective trials and retrospective analyses. Here, we report survival outcomes for patients with metastatic nccRCC treated with IO and/or TT at the Princess Margaret Cancer Centre, Toronto, ON, Canada. Demographics, disease characteristics, and survival outcomes were collected retrospectively. Overall (OS), progression-free survival (PFS), and objective response rates (ORR) were calculated. We identified 69 patients with metastatic nccRCC treated with IO and/or TT as the first-line treatment, and 36 (52.1%) patients as the second-line treatment. Median OS of the first line IO recipients (n = 12) and non-IO recipients (n = 57) was not reached (NR) and 17.2 months (95% confidence interval (95% CI): 7.3-27.0; P = 0.23), respectively. Median PFS of first-line IO recipients and non-IO recipients was NR and 4.7 months (95% CI: 3.7-5.6; P = 0.019), respectively. The ORR of IO recipients versus non-IO recipients was 50% versus 12.3% (P = 0.007). Median OS of the second-line IO recipients (n = 8) and non-IO recipients (n = 28) was NR and 6.3 months (95% CI: 3.2-9.3; P = 0.003), respectively. Median PFS of second-line IO recipients and non-IO recipients was 4.8 months (95% CI: 2.7-6.8) and 2.8 months (95% CI: 1.8-3.7; P = 0.014), respectively. ORR of IO recipients and non-IO recipients was 37.5% and 3.5%, respectively; P = 0.028. While the number of patients included in our retrospective review was small, our analysis suggested that patients with nccRCC have improved survival outcomes with IO treatment. Validation of prospective dataset is required before widespread clinical utilization. [ABSTRACT FROM AUTHOR]

Researchers and sociologists have argued the consequences of standardization vis-à-vis clinical practice guidelines are diverse and argue they should be explored empirically. Sociologists have also argued that "best evidence" for the development of clinical practice guidelines is not restricted to randomized controlled trials and that other forms of knowledge should be embedded in and inform CPGs. There is little research concerning how other types of knowledge are mobilized and taken up in CPGs. This article presents the results of an ethnographic investigation in Canada between 2015 and 2020 of the development of a clinical practice guideline for immunotherapy for food allergy. My research shows that immunotherapy has become the source of controversy regarding whether immunotherapy should be offered in the clinic or remain experimental and whether it should be offered using food or commercial products. I argue that the clinical practice guideline for oral immunotherapy reaffirms what has been previously noted by sociologists; guidelines can serve normative purposes and are not merely technical documents. This case study is unique as it demonstrates how guidelines can serve as "community-making devices" to consolidate "epistemic communities" through the explicit and formal mobilization of ethical principles alongside other forms of "traditional" evidence. The mobilization of a multi-criteria approach that included ethical principles was mobilized in part to counter the de-legitimization and peripheralization of clinical and real food oral immunotherapy. [ABSTRACT FROM AUTHOR]

Biliary tract cancers (BTC) are rare and aggressive tumors with poor prognosis. Radical surgery offers the best chance for cure; however, most patients present with unresectable disease, and among those receiving curative-intent surgery, recurrence rates remain high. While other locoregional therapies for unresectable disease may be considered, only select patients may be eligible. Consequently, systemic therapy plays a significant role in the treatment of BTC. In the adjuvant setting, capecitabine is recommended following curative-intent resection. In the neoadjuvant setting, systemic therapy has mostly been explored for downstaging in borderline resectable tumours, although evidence for its routine use is lacking. For advanced unresectable or metastatic disease, gemcitabine-cisplatin plus durvalumab has become the standard of care, while the addition of pembrolizumab to gemcitabine-cisplatin has also recently demonstrated improved survival compared to chemotherapy alone. Following progression on gemcitabine-cisplatin, several chemotherapy combinations and biomarker-driven targeted agents have been explored. However, the optimum regimen remains unclear, and access to targeted agents remains challenging in Canada. Overall, this article serves as a practical guide for the systemic treatment of BTC in Canada, providing valuable insights into the current and future treatment landscape for this challenging disease. [ABSTRACT FROM AUTHOR]

A key phenomenon in cancer is the establishment of a highly immunosuppressive tumour microenvironment (TME). Despite advances in immunotherapy, where the purpose is to induce tumour recognition and hence hereof tumour eradication, the majority of patients applicable for such treatment still fail to respond. It has been suggested that high immunological activity in the tumour is essential for achieving effective response to immunotherapy, which therefore have led to exploration of strategies that triggers inflammatory pathways. Here activation of the stimulator of interferon genes (STING) signalling pathway has been considered an attractive target, as it is a potent trigger of pro‐inflammatory cytokines and types I and III interferons. However, immunotherapy combined with targeted STING agonists has not yielded sustained clinical remission in humans. This suggests a need for exploring novel adjuvants to improve the innate immunological efficacy. Here, we demonstrate that extracellular vesicles (EVs), derived from activated CD4+ T cells (T‐EVs), sensitizes macrophages to elevate STING activation, mediated by IFNγ carried on the T‐EVs. Our work support that T‐EVs can disrupt the immune suppressive environment in the tumour by reprogramming macrophages to a pro‐inflammatory phenotype, and priming them for a robust immune response towards STING activation. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Several recent randomized trials evaluated the impact of adjuvant immune checkpoint inhibitor (ICI)-based therapy on post-surgical outcomes in renal cell carcinoma (RCC), with disparate results. The objective of this consensus statement is to provide data-driven guidance regarding the use of ICIs after complete resection of clear-cell RCC in a Canadian context. METHODS: An expert panel of genitourinary medical oncologists, urologic oncologists, and radiation oncologists with expertise in RCC management was convened in a dedicated session during the 2022 Canadian Kidney Cancer Forum in Toronto, Canada. Topic statements on the management of patients after surgery for RCC, including counselling, risk stratification, indications for medical oncology referral, appropriate followup, eligibility and management for adjuvant ICIs, as well as treatment options for patients with recurrence who received adjuvant immunotherapy, were discussed. Participants were asked to vote if they agreed or disagreed with each statement. Consensus was achieved if greater than 75% of participants agreed with the topic statement. RESULTS: A total of 22 RCC experts voted on 14 statements. Consensus was achieved on all topic statements. The panel felt patients with clear-cell RCC at increased risk of recurrence after surgery, as per the Keynote-564 group definitions, should be counselled about recurrence risk by a urologist, should be informed about the potential role of adjuvant ICI systemic therapy, and be offered referral to discuss risks and benefits with a medical oncologist. The panel felt that one year of pembrolizumab is currently the only regimen that should be considered if adjuvant therapy is selected. Panelists emphasized current opinions are based on disease-free survival given the available results. Significant uncertainty regarding the benefit and harms of adjuvant therapy remains, primarily due to a lack of consistent benefit observed across similar trials of adjuvant ICI-based therapies and immature overall survival (OS) data. CONCLUSIONS: This consensus document provides guidance from Canadian RCC experts regarding the potential role of ICI-based adjuvant systemic therapy after surgery. This rapidly evolving field requires frequent evidence-based re-evaluation. [ABSTRACT FROM AUTHOR]

Immunotherapy and targeted therapies have been shown to considerably improve long-term survival outcomes in metastatic melanoma patients. Real-world evidence on the uptake of novel therapies and outcomes for this patient population in Canada are limited. We conducted a population-based retrospective cohort study of all metastatic melanoma patients diagnosed in Alberta, Canada (2015–2018) using electronic medical records and administrative data. Information on BRAF testing for patients diagnosed in 2017 or 2018 was obtained through chart abstraction. In total, 434 metastatic melanoma patients were included, of which 110 (25.3%) were de novo metastatic cases. The median age at diagnosis was 66 years (IQR: 57–76) and 70.0% were men. BRAF testing was completed for the majority of patients (88.7%). Among all patients, 60.4%, 19.1%, and 6.0% initiated first-line, second-line, and third-line systemic therapy. The most common therapies were anti-PD-1 and targeted therapies. The two-year survival probability from first-line therapy, second-line therapy, and third-line therapy was 0.50 (95% CI: 0.44–0.57), 0.26 (95% CI: 0.17–0.40), and 0.14 (95% CI: 0.40–0.46), respectively. In the first-line setting, survival was highest for patients that received ipilimumab or ipilimumab plus nivolumab, while targeted therapy had the highest survival in the second-line setting. This study indicates that novel therapies improve survival in the real world but a considerable proportion of patients do not receive treatment with systemic therapy. [ABSTRACT FROM AUTHOR]

Introduction: T cell activation can lead to osteoporosis and while there are several case reports of fractures occurring after immune checkpoint inhibitor (ICI) use, to date, there are no population level studies looking at fracture risk related to ICI use. Methods: Using Alberta Cancer Registry data, we identified all individuals treated with ICI for cancer between September 29, 2010, and March 31, 2019. Linked records from Alberta's healthcare administrative databases were assessed for the presence of fracture diagnostic codes in the year prior to and up to two years after ICI initiation. Fracture rate was stratified based on the time-period before and after ICI initiation. Fracture rates after ICI were compared to baseline. Results: The study cohort consisted of 1600 ICI users (mean age 65.7 years, 60% male). Most patients were treated with an anti-PD-1 agent (73.9%). ICIs were initiated on average 707.8 days after cancer diagnosis. 76 (4.8%) individuals had a remote history of a major fracture, and 141 (8.8%) had been treated with an osteoporosis medication prior to ICI treatment. The fracture rate in the year prior to ICI initiation was 11.3 per 1000 patient-years. The fracture rate in the year after ICI initiation was significantly higher at 27.3 per 1000 patient-years. The fracture rate dropped to 17.6 per 1000 patient-years in the second year after ICI initiation. The incidence rate ratio of sustaining a major fracture in the year after compared to the year prior to ICI initiation was 2.43 (95% CI 1.34–4.27). Conclusions: Fracture risk may be increased in cancer patients early after initiation of ICI, and this may represent a novel immune-related adverse event. [ABSTRACT FROM AUTHOR]

Objective: Lung cancer is associated with the highest incidence and mortality of all cancers. New treatments, called targeted therapies (TT) and immunotherapies (IO), offer higher treatment efficacy and fewer side effects compared to traditional treatments but are accompanied by uncertainty and an unpredictable treatment course. There is a paucity of research on the experiences of individuals living with advanced or metastatic lung cancer receiving TT/IO, and even less is known about the supportive care needs of this population., Methods: Twenty four participants from across Canada participated in semi-structured interviews regarding their supportive care needs. Thematic analysis was utilized to identify their supportive care needs., Results: Qualitative coding identified unmet needs and challenges. All participants indicated difficulties with unmet supportive care needs, including psychological, informational, and practical needs., Conclusions: The exploration of supportive care experiences of patients receiving TT/IO exposes high distress and unmet needs. Results indicate the need for timely and accessible supportive cancer care. Results can inform patient advocacy efforts and the development of new services., (© 2024 The Author(s). Psycho‐Oncology published by John Wiley & Sons Ltd.)

For patients with Mantle Cell Lymphoma (MCL), there is no recognized standard of care for relapsed/refractory (R/R) disease after treatment with a Bruton's tyrosine kinase inhibitor (BTKi). Brexucabtagene autoleucel (brexu-cel) represents a promising new treatment modality in MCL. We explored whether brexu-cel was cost-effective for the treatment of R/R MCL. We developed a partitioned survival mixture cure approach to model the costs and outcomes over a lifetime horizon. The clinical data were derived from the ZUMA-2 clinical trial. The costs were estimated from the publicly available Canadian databases, published oncology literature, and pan-Canadian Oncology Drug Review economic guidance reports. The health state utilities were sourced from the ibrutinib submission to the National Institute for Health and Care Excellence for R/R MCL and supplemented with values from the published oncology literature. In the base case over a lifetime horizon, brexu-cel generated an incremental 9.56 life-years and an additional 7.03 quality-adjusted life-years compared to BSC, while associated with CAD 621,933 in additional costs. The resultant incremental cost-utility ratio was CAD 88,503 per QALY gained compared with BSC. Based on this analysis, we found brexu-cel to be a cost-effective use of healthcare resources relative to BSC for treatment of adult patients with R/R MCL previously treated with a BTKi in Canada, though additional research is needed to confirm these results using longer follow-up data. [ABSTRACT FROM AUTHOR]

The use, safety and effectiveness of crizotinib as part of the management of ROS1-rearranged NSCLC patients in a real-world Canadian clinical cohort was the focus of this retrospective review. Twenty-one ROS1-rearranged patients with advanced/metastatic disease receiving crizotinib between 2014–2020 were identified; crizotinib demonstrated tolerability and effectiveness in this population where outcomes were similar to those described in other crizotinib-treated real-world cohorts, but lower than those of the PROFILE 1001 clinical trial population. Systemic anti-cancer therapy prior to crizotinib initiation occurred in half of the study cohort, with platin-pemetrexed and immune checkpoint inhibitors being most common. Platin-pemetrexed showed good effectiveness in this cohort, but despite high prevalence of upregulated PD-L1 expression, immune checkpoint inhibitors showed poor effectiveness in his cohort. Among all systemic therapies received, crizotinib showed the most effective disease control, although longer intervals between diagnosis and crizotinib initiation were more common among those showing a lack of clinical response to crizotinib, and patients with brain metastases at the time of crizotinib initiation also showed increased diagnosis to crizotinib initiation intervals and decreased clinical response to crizotinib. This study reveals crizotinib has clinical benefit, but timely identification of ROS1-rearrangements and initiation targeted therapies appears important to maximize outcome in this population. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer death in Canada and a significant cause of morbidity for patients and their loved ones. There have been rapid advances in preventing, screening and treating this disease. Here, we present a contemporary review of treatment of non-small cell lung cancer in Canada based on current best practices. The focus of this review is to highlight recent data in screening for lung cancer, management of patients with early and locally-advanced non-small cell lung cancer, as well as management of patients with metastatic disease. There is a special focus on the incorporation of immunotherapy into practice and its associated toxicities. [ABSTRACT FROM AUTHOR]

Aim: To evaluate optimal systemic therapy sequencing (first-line targeted therapy (1L-TT) vs. first-line immunotherapy (1L-IO)) in patients with BRAF-mutated metastatic melanoma. Methods: Nation-wide prospective data of patients with newly diagnosed BRAF-mutated metastatic melanoma were retrieved from the Canadian Melanoma Research Network. Results: Our study included 79 and 107 patients in the 1L-IO and 1L-TT groups, respectively. There were more patients with ECOG 0–1 (91% vs. 72%, p = 0.023) in the 1L-IO group compared to the 1L-TT group. Multivariable Cox analysis suggested no OS differences between the two groups (HR 0.838, 95%CI 0.502–1.400, p = 0.500). However, patients who received 1L-TT then 2L-IO had the longest OS compared to 1L-IO without 2L therapy, 1L-IO then 2L-TT, and 1L-TT without 2L therapy (38.3 vs. 32.2 vs. 16.9 vs. 6.3 months, p < 0.001). For patients who received 2L therapy, those who received 2L-IO had a trend towards OS improvement compared with the 2L-TT group (21.7 vs. 8.9 months, p = 0.053). Conclusions: Our nation-wide prospective study failed to establish any optimal systemic therapy sequencing in advanced BRAF-mutant melanoma patients. Nevertheless, we provided evidence that immunotherapy has durable efficacy in advanced BRAF-mutant melanoma patients, regardless of treatment line, and that Canadian medical oncologists were selecting the appropriate treatment sequences in a real-world setting, based on patients' clinical and tumour characteristics. [ABSTRACT FROM AUTHOR]

Objective: This study aims to analyze the 100 most cited papers and research trends on stereotactic body radiotherapy (SBRT). Methods: We used Web of Science to identify the 100 most frequently cited papers on SBRT on September 29, 2021 and extracted the following data: publication year, source title, country/region, organization, total citations, and average number of citations per year. The research type and research domain were classified independently by the authors. Then we carried out a bibliometric analysis to determine the trends in research on SBRT. Results: These 100 papers were cited a total of 26,540 times, and the median number of citations was 190 (range, 138-1688). "Stereotactic body radiation therapy for inoperable early stage lung cancer" by Timmerman et al. had the highest number of total citations (1688 times). International Journal of Radiation Oncology, Biology, Physics published the largest number of papers (37 papers), followed by Journal of Clinical Oncology (13 papers). The USA contributed the most papers (67 papers), followed by Canada (18 papers). Primary lung cancer (33 papers, 10,683 citations) and oligometastases (30 papers, 7,147 citations) were the most cited research areas. Conclusions: To the best of our knowledge, this is the first bibliometric analysis of the most frequently cited papers on SBRT. Our results provide insight into the historical development of SBRT and important advances in its application to cancer treatment. Early-stage non–small-cell lung cancer and oligometastases were the most cited research areas in the top 100 publications on SBRT, and SBRT combined with immunotherapy was a hot topic in the past few years. This study is helpful for researchers to identify the most influential papers and current research hotspots on SBRT. [ABSTRACT FROM AUTHOR]

Immunotherapy-based systemic treatment (ST) is the standard of care for most patients diagnosed with metastatic renal cell carcinoma (mRCC). Cytoreductive nephrectomy (CN) has historically shown benefit for select patients with mRCC, but its role and timing are not well understood in the era of immunotherapy. The primary objective of this study is to assess outcomes in patients who received ST only, CN followed by ST (CN-ST), and ST followed by CN (ST-CN). The Canadian Kidney Cancer information system (CKCis) database was queried to identify patients with de novo mRCC who received immunotherapy-based ST between January 2014 and June 2023. These patients were classified into three categories as described above. Cox proportional hazards models were used to assess the impact of the timing of ST and CN on overall survival (OS) and progression-free survival (PFS), after adjusting for the International Metastatic RCC Database Consortium (IMDC) risk group, age, and comorbidities. Best overall response and complications of ST and CN for these cohorts were collected. A total of 588 patients were included in this study: 331 patients received ST only, 215 patients received CN-ST, and 42 patients received ST-CN. Patient and disease characteristics including age, gender, performance status, IMDC risk category, comorbidity, histology, type of ST, and metastatic sites are reported. OS analysis favored patients who received ST-CN (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.13-0.68) and CN-ST (HR 0.68, CI 0.47-0.97) over patients who received ST only. PFS analysis showed a similar trend for ST-CN (HR 0.45, CI 0.26-0.77) and CN-ST (HR 0.9, CI 0.68-1.17). This study examined baseline features and outcomes associated with the use and timing of CN and ST using real-world data via a large Canadian real-world cohort. Patients selected to receive CN after ST demonstrated improved outcomes. There were no appreciable differences in perioperative complications across groups. Limitations include the small number of patients in the ST-CN group and residual confounding and selection biases that may influence the outcomes in patients undergoing CN.

Objectives: KRAS mutations, particularly KRAS G12C , are prevalent in non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) have been a frontline treatment, but recently developed KRAS G12C -selective inhibitors, such as sotorasib, present new therapeutic options. We conducted a multi-center retrospective cohort study to gain insights into real-world treatment patterns and outcomes in patients with KRAS G12C -positive advanced NSCLC receiving systemic therapy post-ICI treatment., Methods: From the CAnadian CAncers With Rare Molecular Alterations-Basket Real-world Observational Study (CARMA-BROS), a cohort of 102 patients with KRAS G12C -positive advanced NSCLC across 9 Canadian centers diagnosed between 2015 and 2021 was analyzed. Clinico-demographic and treatment data were obtained from electronic health records. Survival outcomes were assessed using Kaplan-Meier curves and Cox proportional hazards models., Results: The patients (median age 66 years; 58 % female; 99 % current/former tobacco exposure; 59 % PD-L1 ≥ 50 %), exhibited heterogeneous treatment patterns post-ICI. Most patients received ICIs as a first-line therapy, with varying subsequent lines including chemotherapy and targeted therapy. In patients receiving systemic therapy post-ICI, median overall survival was 12.6 months, and real-world progression-free survival was 4.7 months. KRAS G12C -selective targeted therapy post-ICI (n = 20) showed longer real-world progression-free survival compared to single-agent chemotherapy (aHR = 0.39, p = 0.012)., Conclusion: This study contributes valuable real-world data on KRAS G12C -positive advanced NSCLC post-ICI treatment. The absence of a standard treatment sequencing post-ICI underscores the need for further investigation and consensus-building in the evolving landscape of KRAS G12C -targeted therapies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The study was supported by Amgen. The authors have no other conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Venous thrombotic events (VTEs) are a frequent complication of non-small cell lung cancer (NSCLC) and are associated with increased morbidity. Immune checkpoint inhibitors (ICIs) are revolutionizing the management of NSCLC, but little is known about their impact on thrombosis. This study aims to define the incidence and clinical relevance of VTEs in NSCLC patients receiving these treatments. A retrospective multicentric cohort study including 593 patients from three centers in Canada and France was performed. The cumulative incidence of VTEs after ICIs was estimated using competing risk analysis, and the association of these events with survival and response to treatment was determined. Finally, univariate and multivariate tests were performed to identify VTE risk factors. The cumulative incidence of VTEs in the cohort was 14.8% (95% CI = 7.4–22.2%) for an incidence rate of 76.5 (95% CI = 59.9–97.8) thrombosis per 1000 person-years, with most thromboses occurring rapidly after treatment initiation. VTEs were not correlated with overall survival, progression-free survival, or objective response to ICIs. Age ˂ 65 years old (HR = 2.00; 95% CI = 1.11–3.59) and tumors with PD-L1 1–49% (HR = 3.36; 95% CI = 1.19–9.50) or PD-L1 ≥ 50% (HR = 3.22; 95% CI = 1.21–8.57) were associated with more VTEs after 12 months of ICI initiation. Also, a delay of less than 12 months from diagnosis to the first ICI treatment (HR = 2.06; 95% CI = 1.09–3.89) and active smoking (HR = 2.00; 95% CI = 1.12–3.58) are probable risk factors of VTEs. This study suggests that the incidence of VTEs in NSCLC patients treated with ICIs is comparable to what is reported in other cohorts of patients treated with chemotherapy. In our cohort, VTEs were not associated with a decreased survival or response to therapy. Patient age < 65 and tumors with PD-L1 ≥ 1% were associated with a higher risk of VTEs under ICIs. • Venous thrombosis is common in NSCLC patients receiving immune checkpoint inhibitors. • Comparable incidence of venous thrombosis under immunotherapy and chemotherapy • No association between venous thrombosis and clinical response to immunotherapy • Higher risk of venous thrombosis when age < 65 years and tumor PD-L1 ≥ 1% • Likely higher risk of venous thrombosis if diagnosis <12 months and active smoking [ABSTRACT FROM AUTHOR]

Background: Leukopenia occurs frequently following kidney transplantation and is associated with adverse clinical outcomes including increased infectious risk. In this study we sought to characterize the causes and complications of leukopenia following kidney transplantation. Methods: In a cohort of adult patients (≥18 years) who underwent kidney transplant from Jan 2006-Dec 2017, we used univariable Cox proportional Hazards models to identify predictors of post-transplant leukopenia (WBC < 3500 mm3). Factors associated with post-transplant leukopenia were then included in a multivariable backwards stepwise selection process to create a prediction model for the outcome of interest. Cox regression analyses were subsequently used to determine if post-transplant leukopenia was associated with complications. Results: Of 388 recipients, 152 (39%) developed posttransplant leukopenia. Factors associated with leukopenia included antithymocyte globulin as induction therapy (HR 3.32, 95% CI 2.25-4.91), valganciclovir (HR 1.84, 95% CI 1.25-2.70), tacrolimus (HR 3.05, 95% CI 1.08-8.55), prior blood transfusion (HR 1.17 per unit, 95% CI 1.09- 1.25), and donor age (HR 1.02 per year, 95% CI 1.00-1.03). Cytomegalovirus infection occurred in 26 patients with leukopenia (17.1%). Other than cytomegalovirus, leukopenia was not associated with posttransplant complications. Conclusion: Leukopenia commonly occurred posttransplant and was associated with modifiable and non-modifiable pretransplant factors. [ABSTRACT FROM AUTHOR]

Background: Limited data are available on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with preexisting autoimmune diseases (PAD). Methods: Retrospective study of patients with PAD referred for rheumatologic evaluation prior to starting or during immunotherapy between January 2013 and July 2019 from 10 academic sites across Canada. Data were extracted by chart review using a standardized form. Results: Twenty-seven patients with PAD on ICI therapy were identified. The most common PADs were rheumatoid arthritis (30%), psoriasis/psoriatic arthritis (30%), inflammatory bowel disease (IBD, 15%) and axial spondyloarthritis (11%), and the most frequently observed cancers were lung cancer and melanoma. All patients received anti-PD-1 therapies, and 2 received additional sequential anti-CTLA-4 therapy. PAD exacerbations occurred in 52% over a median (IQR) follow-up of 11.0 (6.0–17.5) months, with 14% being severe, 57% requiring corticosteroids, 50% requiring immunosuppression and 14% requiring ICI discontinuation. Flares were generally more frequent and severe in patients who previously required more intensive immunosuppression (i.e., biologics). Flares occurred despite background immunosuppression at the time of ICI initiation. In patients with preexisting psoriasis, IBD and axial spondyloarthritis, rheumatic immune-related adverse events (irAEs), mostly polyarthritis and tenosynovitis, were frequently observed. Tumor progression was not associated with exposure to immunosuppressive drugs before or after ICI initiation and was numerically less frequent in patients with irAEs. Conclusion: PAD exacerbations in the context of ICI treatment are common, although generally mild, and occur despite background immunosuppression. Exacerbations are more frequent and severe in patients on more intensive immunosuppressive therapies pre-immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy. Materials and Methods: Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post‐CBT treatment using the Lugano criteria. Secondary aims included progression‐free survival (PFS), duration of response, and overall survival (OS). Results: Eighty‐one patients were included. Seventy‐two percent had stage III–IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post‐CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post‐CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post‐CBT regimen. Conclusion: In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post‐CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials. Implications for Practice: Novel, life‐prolonging treatment strategies in relapsed and refractory (R/R) Hodgkin lymphoma (HL) are greatly desired. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy (CBT) use in R/R HL may sensitize patients to their subsequent treatment. This approach may potentially enhance therapeutic options or to bridge patients to transplant. Prospective data are warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment‐related toxicity and thus improve patient quality of life. This study investigated the outcome of checkpoint blockade therapy on subsequent treatment for patients with relapsed and refractory Hodgkin lymphoma in a large, multicenter, retrospective analysis. [ABSTRACT FROM AUTHOR]

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The article discusses evidence-based changes in the first-line treatment of patients with stage IV lung cancer and reflects a shifting paradigm for the subset of patients whose Non-Small-Cell Lung Cancer is without actionable mutation away from primarily solely cytotoxic chemotherapy.

Background: Previous proof-of-concept studies have shown that a short course of omalizumab can safely accelerate the oral immunotherapy schedule for multiple allergens simultaneously. Considering the high cost of medication, the dose-related efficacy of omalizumab at decreasing the duration of oral immunotherapy up-dosing phase must be objectively quantified before cost–benefit analyses can be performed. The primary objective of this trial will be to compare the efficacy of 2 omalizumab dosages to placebo at decreasing time-to-maintenance dose during a symptom-driven multi-food OIT protocol. Methods: A total of 90 participants aged 6 to 25 with multiple food allergies (3 or more) will be enrolled at four sites in Canada. Participants will be randomized to: (A) Omalizumab 8 mg/kg per month (n = 36); (B) Omalizumab 16 mg/kg per month (n = 36); or (C) Placebo (n = 18). Study drug will be administered at full dosage for 12 weeks, then progressively tapered at 50% dosage (8 mg/kg vs 4 mg/kg vs placebo) for 4 weeks and at 25% dosage (4 mg/kg vs 2 mg/kg vs placebo) for another 4 weeks. After a pre-treatment period of 8 weeks, participants will undergo an initial food escalation (IFE) to an OIT mix containing 3 allergens and start daily home dosing with biweekly increases until a target daily maintenance of 1500 mg protein is achieved. The amount escalated at each visit will vary based on treatment tolerance according to a standardized up-dosing algorithm. Participants will be followed for at least 12 months following the initial food escalation. The primary endpoint will be time from IFE to the target maintenance dose of 1500 mg protein. Time-to-event analytic methods, including the log-rank test, will be used to compare the 3 arms. Discussion: This trial uses a novel pragmatic approach to compare OIT with omalizumab to OIT without omalizumab in a blinded manner, which allows to single out the effect of this anti-IgE medication on treatment effectiveness speed without the recourse to predetermined schedules. The innovative patient-centered up-dosing algorithm allows to maximise treatment effectiveness speed without compromising patient safety, regardless of whether the patient is on omalizumab or not. This study will also provide novel prospective data to inform on the optimal and most cost-effective dosage for this indication. Trial registration ClinicalTrials.gov, NCT04045301, Registered 5 August 2019, https://clinicaltrials.gov/ct2/show/NCT04045301 [ABSTRACT FROM AUTHOR]

Lung cancer is the most commonly diagnosed cancer in Canada and remains associated with high mortality. Nevertheless, recent advances in the fields of immuno-oncology and precision medicine have led to significant improvements in clinical outcome in metastatic non-small-cell lung cancer (nsclc). Those improvements were facilitated by a greater understanding of the biologic classification of nsclc, which catalyzed discoveries of novel therapies. Here, we present a comprehensive review of the recent avalanche of practice-changing trials in metastatic nsclc, and we offer an approach to the management of this disease from a Canadian perspective. We begin with an overview of the pathologic and molecular characterization of metastatic nsclc. Next, we review the indications for currently approved immune checkpoint inhibitors, and we provide an approach to the management of disease with a driver mutation. Finally, we address future avenues in both diagnostics and therapeutics for patients with advanced and metastatic nsclc. [ABSTRACT FROM AUTHOR]

2′, 3′-cGAMP (CDN) as cGAS-STING pathway agonist is extensively used in tumor treatment. However, due to its negatively charged nature (containing two phosphate groups) and high hydrophilicity, CDN faces challenges in crossing cell membranes, resulting in reduced efficiency of its use. Additionally, CDN is susceptible to inactivation through phosphodiesterase hydrolysis. Therefore, the development of a new drug delivery system for CDN is necessary to prevent hydrolysis and enhance targeted accumulation in tumors, as well as improve cellular uptake for STING activation. In this study, we have developed peptide-polymer nanofibers (PEG-Q11) that incorporate thymine (T) and arginine (R) residues to facilitate complexation with CDN through the principles of Watson-Crick base pairing with thymine and favorable electrostatic interactions and bidentate hydrogen bonding with arginine side chains. The entrapment efficiency (EE) of PEG-Q11T3R4@CDN was found to be 51% higher than that of PEG-Q11@CDN. Due to its favorable biocompatibility, PEG-Q11T3R4@CDN was employed for immunotherapy in mouse CT26 tumors. In local tumor treatment, the administration of PEG-Q11T3R4@CDN at a low dose and through a single injection exhibited inhibitory effects. Furthermore, the local injection of PEG-Q11T3R4@CDN resulted in systemic therapeutic responses, effectively suppressing tumor metastasis by activating CD8 + T cells to target distant tumors. This research not only underscores the potential of PEG-Q11T3R4@CDN as an efficient therapeutic agent but also highlights its ability to achieve long-lasting systemic therapeutic outcomes following local treatment. Consequently, PEG-Q11T3R4@CDN represents a promising strategy for immunization. • A nucleobase was used to modify self-assembled peptide loading CDN for the first time. • The new platform interacted with CDN via H-bonding and favorable electrostatic interactions to improve the dose of CDN loaded. • The new platform boosted the effect of CDN release, and realized a single administration of CDN. • The new platform strongly influenced tumor immunotherapy in proximal and distal tumors. [ABSTRACT FROM AUTHOR]

Cost effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma. The patient is monitored for cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndrome for up to 28 days and monitored long term for B-cell hypoplasia, hypogammaglobulinemia, cytopenias and opportunistic infections. Most patients with relapsed refractory high-grade B-cell lymphoma and B-cell acute lymphoblastic leukemia have progression-free and overall survival rates better than historical controls, and a small proportion are cured. Chimeric antigen receptor T-cell therapy (CAR-T) is a targeted, gene-edited cell therapy for cancer that is approved in Canada for relapsed or refractory high-grade B-cell lymphoma and B-cell acute lymphoblastic leukemia. [Extracted from the article]

From 19 to 21 November 2022, BioCanRx held its first post-pandemic in-person Summit for Cancer Immunotherapy in Montreal, Canada. The meeting was well attended by patients, trainees, researchers, clinicians, and industry professionals, who came together to discuss the current state and future of biotherapeutics for cancer in Canada and beyond. Three plenaries, three keynote speakers, a lively debate, and panel discussions, together with poster sessions and a social event, made the event memorable and productive. The current state of cellular therapies, cellular engineering, clinical trials, and the role of the cancer microbiome were discussed in plenary session, and the patient voice was welcomed and present throughout the meeting, in large part due to the Learning Institute, a BioCanRx initiative to include patient partners in research. In this meeting review, we highlight the platform presentations, keynote speakers, debate combatants, panellists, and the patient perspective on the annual meeting., Competing Interests: The authors declare there are no competing interests.

Immunotherapy for cancer treatment continues to evolve, and immune checkpoints have proven successful therapeutic targets. With success has come the challenge of managing the commonly associated immune-related toxicities. Arthralgias and arthritis are a common immune-related adverse event (IrAE), well described in the literature (Pardoll Nat Rev Cancer 12:252–264, 2012; Diesendruck and Benhar Drug Resist Updat 30:39–47, 2017; Cappelli et al. Arthritis Care Res 69:1751–1763, 2017; Brahmer et al. J Clin Oncol 36:1714–1768, 2018; Smith and Bass (2017). The optimal management of immune checkpoint inhibitor (ICI)–induced arthritis remains unclear. We describe the first series using hydroxychloroquine as a first-line disease-modifying antirheumatic drug (DMARD) for patients without pre-existing autoimmune disease, who developed arthritis secondary to ICI's. This was a single-center retrospective observational study reporting all patients evaluated by rheumatologists affiliated with the University of Alberta, a large tertiary health care center in Northern Alberta, Canada, deemed to have inflammatory arthritis (IA) following ICIs. We identified 11 patients, without pre-existing autoimmune disease, who developed IA following ICIs. Most patients presented with a symmetrical polyarthritis with both large and small joint involvement. All patients were treated according to the outlined treatment protocol with hydroxychloroquine as a first-line steroid-sparing agent: either as monotherapy or in combination with tapering doses of systemic corticosteroids (3) or intra-articular steroid injections (6). One patient required the addition of methotrexate to control symptoms and none required biologic therapy. There were no reported adverse effects from hydroxychloroquine. Inflammatory arthritis is an important complication of ICIs leading to significant impact on patient quality of life. In our experience, in patients without pre-existing autoimmune disease, hydroxychloroquine is an effective first-line therapy for IA secondary to ICI therapy. [ABSTRACT FROM AUTHOR]

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2023 was held in Quebec City, Quebec 2-4 February 2023. The purpose of the conference was to develop consensus statements on emerging and evolving treatment paradigms. Participants included Canadian medical oncologists, radiation oncologists, pathologists and surgical oncologists from across Ontario, Quebec, and the Atlantic provinces. Consensus statements were developed following rapid review presentations and discussion of available literature. The recommendations proposed here represent the consensus opinions of physicians involved in the care of patients with gastrointestinal malignancies who participated in this meeting.

Background The development and approval of both targeted and immune therapies for patients with advanced non-small cell lung cancer (nsclc) has significantly improved patient survival rates and quality of life. Biomarker testing for patients newly diagnosed with nsclc, as well as for patients progressing after treatment with epidermal growth factor receptor (EGFR) inhibitors, is the standard of care in Canada and many parts of the world. Methods A group of thoracic oncology experts in the field of thoracic oncology met to describe the standard for biomarker testing for lung cancer in the Canadian context, focusing on evidence-based recommendations for standardof- care testing for EGFR, anaplastic lymphoma kinase (ALK), ROS1, BRAF V600 and programmed death-ligand (PDL1) at the time of diagnosis of advanced disease and EGFR T790M upon progression. As well, additional exploratory molecules and targets are likely to impact future patient care, including MET exon 14 skipping mutations and whole gene amplification, RET translocations, HER2 (ERBB2) mutations, NTRK, RAS (KRAS and NRAS), as well as TP53. Results The standard of care must include the incorporation of testing for novel biomarkers as they become available, as it will be difficult for national guidelines to keep pace with technological advances in this area. Conclusions Canadian patients with nsclc should be treated equally; the minimum standard of care is defined in this paper. [ABSTRACT FROM AUTHOR]

The 2017 PACIFIC trial heralded the incorporation of routine adjuvant durvalumab following curative-intent chemoradiation for stage III non-small-cell lung cancer (NSCLC). However, carefully selected clinical trial populations can differ significantly from real-world populations, which can have implications on treatment toxicities and outcomes, making it difficult to accurately counsel patients. Consequently, we performed a real-world, retrospective analysis of outcomes and toxicities in 118 patients with stage III NSCLC treated with durvalumab after platinum-based chemoradiotherapy. The data were collected from patients who underwent treatment at a single, tertiary-level Canadian cancer centre from May 2018 to October 2020. The variables collected included patient demographics, treatment specifics, progression-free survival, overall survival, and immune-related adverse events (IRAE) from durvalumab. Descriptive statistics were used for toxicity analysis, and progression-free survival and overall survival estimates were calculated using the Kaplan-Meier method. The statistical analyses indicated a 64.4% ( n = 76) toxicity rate, with a 21% ( n = 25) toxicity rate of grade 3+ IRAEs. The most common documented IRAEs were pneumonitis ( n = 44; 40%), followed by rash ( n = 20; 18%) and thyroid dysfunction ( n = 17; 15%). FEV1 and DLCO were not found to be associated predictors of pneumonitis toxicity. The median PFS and OS were estimated to be >1.7 years and >2.7 years, respectively.

Objectives: Thoracic radiation therapy (TRT) and prophylactic cranial irradiation (PCI) are commonly used in the management of extensive-stage small-cell lung cancer (ES-SCLC); however, Phase III trials of first-line immunotherapy often excluded these options. Guidance is needed regarding appropriate use of TRT, PCI, and magnetic resonance imaging (MRI) surveillance while new data are awaited., Materials and Methods: In two web-based meetings, a pan-Canadian expert working group of five radiation oncologists and four medical oncologists addressed eight clinical questions regarding use of radiation therapy (RT) and MRI surveillance among patients with ES-SCLC receiving immunotherapy. A targeted literature review was conducted using PubMed and conference proceedings to identify recent (January 2019-April 2022) publications in this setting. Fifteen recommendations were developed; online voting was conducted to gauge agreement with each recommendation., Results: After considering recently available evidence across lung cancer populations and clinical experience, the experts recommended that all patients with a response to chemo-immunotherapy, good performance status (PS), and limited metastases be considered for consolidation TRT (e.g., 30 Gy in 10 fractions). When considered appropriate after multidisciplinary team discussion, TRT can be initiated during maintenance immunotherapy. All patients who respond to concurrent chemo-immunotherapy should undergo restaging with brain MRI to guide decision-making regarding PCI versus MRI surveillance alone. MRI surveillance should be conducted for two years after response to initial therapy. PCI (e.g., 25 Gy in 10 fractions or 20 Gy in 5 fractions) can be considered for patients without central nervous system involvement who have a response to chemo-immunotherapy and good PS. Concurrent treatment with PCI and immunotherapy or with TRT, PCI, and immunotherapy is appropriate after completion of initial therapy. All recommendations were agreed upon unanimously., Conclusions: These consensus recommendations provide practical guidance regarding appropriate use of RT and immunotherapy in ES-SCLC while awaiting new clinical trial data., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A. Sun has received honoraria from and participated in advisory boards with AstraZeneca. B. Abdulkarim has no conflicts to disclose. N. Blais reports receiving consulting fees from AstraZeneca. J. Greenland has received honoraria from AstraZeneca for attendance at advisory boards. A.V. Louie reports receiving honoraria from AstraZeneca for a speakers bureau and an advisory board. B. Melosky has received honoraria from AstraZeneca, BMS, Merck, and Roche. D. Schellenberg reports receiving institutional grants from Varian Medical Systems and payments from AstraZeneca, Merck, and Pfizer for presentations/educational events and advisory board participation. He also reports participation in Linear Accelerator selection for BC Cancer and receipt of a class action lawsuit payment from Medtronic. S. Snow reports research/trial funding paid to her institution by AstraZeneca, BMS, Merck, Novartis, Sanofi, and Takeda and receiving consulting fees from Novartis and Roche. She has also received honoraria for lectures and presentations at educational events from Amgen, AstraZeneca, Bayer, BMS, Elvium Life Sciences, Jazz Pharmaceuticals, Pfizer, and Taiho. S. Snow has also participated in advisory boards for Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, EMD Serono, Janssen, Jazz Pharmaceuticals, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda, and Taiho, and was the President of Lung Cancer Canada and on its Board of Directors at the time of publication. G. Liu has received institutional research grants from NCI (US), CIHR (Canada), CCSRI (Canada), Amgen, AstraZeneca, Boehringer Ingelheim, and Takeda. He has received payment or honoraria from AstraZeneca, EMD Serono, Jazz Pharmaceuticals, Novartis, Pfizer, and Takeda, and has participated in data safety monitoring boards or advisory boards with AbbVie, AstraZeneca, BMS, EMD Serono, Jazz Pharmaceuticals, Eli Lilly, Merck, Novartis, Pfizer, Roche, and Takeda., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background The lack of glomerulonephritis (GN) guidelines has historically contributed to substantial variability in the treatment of GN. We hypothesize that there are barriers to GN guideline implementation leading to incomplete translation of the 2012 KDIGO GN guidelines into patient care, and that current practice patterns deviate from guideline recommendations. Methods Adult nephrologists in Canada (N = 390) were surveyed using a web-based tool. The survey of 40 questions captured physician demographics, self-reported GN case load, treatment approaches and barriers to guideline implementation. Results The response rate was 44%. Physicians report seeing six (IQR 4,10) new cases of idiopathic GN every 6 months. The majority treat ANCA GN according to guidelines, but 9–37% treat nephrotic focal segmental glomerulosclerosis or membranous nephropathy with non-recommended immunosuppression and 6–9% do not treat with any immunotherapy, whereas 26% treat subnephrotic disease with immunosuppression. The majority indicated that standardized care tools would improve patient care, but they were only available to 25–44%. Patient education tools and nursing support are unavailable to 87 and 67%, respectively; insurance coverage for immune therapies is poorly accessible to 84%, yet 86% feel this would improve care and 96% of physicians support comparing their practice with benchmarks from provincial GN registries. Conclusions We show that 2 years after the publication of the KDIGO GN guidelines, 15–46% of Canadian nephrologists report treatment strategies not in keeping with guideline recommendations. We identify barriers to guideline implementation and widespread physician support for initiatives that address these barriers to improve patient care. [ABSTRACT FROM AUTHOR]

The activation of stimulator of interferon genes (STING) signaling pathways plays an important role in the innate immune response. Although several STING agonists have been developed recently, the majority of clinical CDN STING agonists are administered by intratumoral (IT) injection. Therefore, there remains a need to develop diverse non-CDN small-molecule STING agonists with systemic administration. Herein, by using a scaffold hopping strategy, we designed a series of thieno [2,3-d]imidazole derivatives as novel STING agonists. Further structure-activity relationship study and optimization led to the discovery of compound 45 as a highly potent human STING agonist with an EC 50 value of 1.2 nM. Compound 45 was found to bind to multiple human STING isoforms and accordingly activated the downstream TBK1/IRF3 and NF-κB signaling pathways in the reporter cells bearing with different STING isoforms. The activation on STING signaling pathway was abolished in the STING knock-out cells, indicating that it is a specific STING agonist. Compound 45 significantly inhibited the tumor growth in allograft 4T1 and CT26 tumor models by systemic administration, and more significantly, 45 was able to induce tumor regression in CT26 tumor model without inducing weight loss, suggesting that compound 45 is a highly promising candidate worthy for further development. [Display omitted] • A series of thieno [2,3-d]imidazole derivatives were designed as STING agonists. • 45 was able to activate h-STING isoforms and m-STING. • 45 was identified as a highly potent h-STING agonist with an EC 50 value of 1.2 nM. • Intravenous or intratumoral administration of 45 could inhibit tumor growth dramatically, without inducing weight loss. [ABSTRACT FROM AUTHOR]

Disease surveillance can be used as an opportunity to determine priorities for research and the development of new therapeutics. This is evident in the work underway to develop a new vaccine to combat a serious invasive childhood disease: Haemophilus influenzae serotype a (Hia). Following the introduction of Hib vaccine into the routine childhood immunization schedule in Canada in the early 1990's, the Public Health Agency of Canada (PHAC) began to document the dropping rates of H influenzae serotype b (Hib) infection. However, invasive H. influenzae diseases due to non-Hib strains began to increase and in 2007, surveillance for invasive H. influenzae disease due to all serotypes as well as non-typeable strains was initiated. Current data suggests Hia is a cause of serious invasive disease, particularly in Aboriginal populations. Similar to Hib, Hia causes severe illnesses such as meningitis, sepsis and bacteremic pneumonia in young children under the age of five. Given the emerging threat due to Hia in Aboriginal populations in Canada, PHAC formed a partnership with the National Research Council of Canada (NRC) to investigate the potential of creating a capsular polysaccharide vaccine against Hia. At the present time, candidate vaccine seed strains have been identified and PHAC and the NRC are working with the Northern Ontario School of Medicine, the US Centers for Disease Control and Prevention and others. The goal of this research is to identify and prepare a candidate vaccine against Hia while increasing the understanding of how such a vaccine would improve the health of a vulnerable population. [ABSTRACT FROM AUTHOR]

The article reports on the new active vaccine recommendations presented by the National Advisory Committee on Immunization (NACI), the scientific advisory body on immunization for the Public Health Agency of Canada. It is said that NACI develops guideline for the use of vaccines for Canadians, which are published in the Canadian Immunization Guide (the Guide).

Biliary tract cancer (BTC) is a group of rare and aggressive malignancies with a dismal prognosis. There is currently a significant lack in effective treatment options for BTC, with gemcitabine-cisplatin remaining the first-line standard of care treatment for over a decade. A wave of investigational therapies, including new chemotherapy combinations, immunotherapy, and biomarker-driven targeted therapy have demonstrated promising results in BTC, and there is hope for many of these therapies to be incorporated into the Canadian treatment landscape in the near future. This review discusses the emerging therapies under investigation for BTC and provides a perspective on how they may fit into Canadian practice, with a focus on the barriers to treatment access.

BACKGROUNDLimited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID).METHODSThis observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, or psoriatic disease, with or without maintenance immunosuppressive therapies. Ab and T cell responses to SARS-CoV-2, including neutralization against SARS-CoV-2 variants, were determined before and after 1 and 2 vaccine doses.RESULTSWe prospectively followed 150 subjects, 26 healthy controls, 9 patients with IMID on no treatment, 44 on anti-TNF, 16 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 10 on anti-IL-23, 28 on anti-IL-12/23, 9 on anti-IL-17, and 8 on MTX/AZA. Ab and T cell responses to SARS-CoV-2 were detected in all participants, increasing from dose 1 to dose 2 and declining 3 months later, with greater attrition in patients with IMID compared with healthy controls. Ab levels and neutralization efficacy against variants of concern were substantially lower in anti-TNF-treated patients than in healthy controls and were undetectable against Omicron by 3 months after dose 2.CONCLUSIONSOur findings support the need for a third dose of the mRNA vaccine and for continued monitoring of immunity in these patient groups.FUNDINGFunded by a donation from Juan and Stefania Speck and by Canadian Institutes of Health (CIHR)/COVID-Immunity Task Force (CITF) grants VR-1 172711 and VS1-175545 (to THW and ACG), CIHR FDN-143250 (to THW), GA2-177716 (to VC, ACG, and THW), and GA1-177703 (to ACG) and the CIHR rapid response network to SARS-CoV-2 variants, CoVaRR-Net (to ACG).

Introduction: Ipilimumab plus nivolumab was associated with a survival benefit in a phase III clinical trial of first-line treatment for metastatic renal cell carcinoma (mRCC). In this study, mRCC patients from the Canadian Kidney Cancer Information System (CKCis) database who received first-line ipilimumab plus nivolumab were analyzed to determine the safety and outcomes in a real-world setting., Patients and Methods: Patients who received ipilimumab plus nivolumab as first-line therapy for mRCC in CKCis, were identified, and the amount of treatment received, discontinuation rates, and reasons for discontinuing treatment were determined. Toxicity data, including type and grade, were collected. Efficacy outcomes of interest included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR)., Results: The cohort included 195 patients, the majority with clear cell histology (74%). All 4 cycles of ipilimumab plus nivolumab were administered in 124 patients (64%). Progressive disease (n = 87; 45%) and toxicity (n = 36; 18%) were the most common causes for discontinuing treatment. Several patients (n = 18) did not receive all 4 doses of ipilimumab but received single agent nivolumab. The estimated median OS was 54.5 months (95% CI, 17.7 - NE) and 12-month OS was 72.2% (95% CI, 65.0 - 79.3). Median PFS was 7.4 months (95% CI 5.3 - 10.2) and ORR was 42.5%. Patients who received all 4 cycles of ipilimumab plus nivolumab had better ORR (50% vs. 28%) and a longer PFS and OS than those who received less than 4 cycles (P < .0001). Ninety-five AEs were documented in 72 patients who required dose reduction/change, with colitis being the most frequent., Conclusion: In this real-world cohort of treatment-naïve mRCC patients, outcomes, and safety were comparable to previously reported clinical trial data., (Copyright © 2021. Published by Elsevier Inc.)

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 (ICSs) represent the standard of care for the majority of patients. Combination ICS/long-acting beta2-agonists (LABA) inhalers are preferred for most adults who fail to achieve control with ICS therapy. 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. Regular monitoring of asthma control, adherence to therapy and inhaler technique are also essential components of asthma management. This article provides a review of current literature and guidelines for the appropriate diagnosis and management of asthma. [ABSTRACT FROM AUTHOR]