Real-word experience of pazopanib and sorafenib in patients with desmoid tumors: A CanSaRCC multi-center study.

BACKGROUND: Sorafenib and pazopanib, two tyrosine kinase inhibitors (TKI), are widely used in patients with progressive symptomatic desmoid tumors (DT). Limited real-word data is available on long-term outcomes of patients who progressed on, stopped, or continued TKIs. METHODS: Patients diagnosed with DTs and treated with sorafenib or pazopanib between 2011 and 2022 at 11 institutions were reviewed. Patient history, response to therapy and toxicity were recorded. Statistical analyses utilized Kaplan-Meier and log-rank tests. RESULTS: 142 patients with DT treated with sorafenib (n = 126, 88.7 %) or pazopanib (n = 16, 11.3 %) were analyzed. The median treatment duration was 10.8 months (range: 0.07- 73.9). The overall response rate and the disease control rate were 26.0 % and 95.1 %, respectively. The median tumor shrinkage was - 8.5 % (range -100.0 %- +72.5 %). Among responders, the median time to an objective response was 15.2 months (range: 1.1 to 33.1). The 1-year and 2-year progression-free survival rates were 82 % and 80 %. Dose reductions were necessary in 34 (23.9 %) patients. Grade 3 or higher adverse events were reported in 36 (25.4 %) patients. On the last follow-up, 55 (38.7 %) patients continued treatment. Treatment discontinuation (n = 85, 59.9 %) was mainly for toxicity (n = 35, 45.9 %) or radiological or clinical progression (n = 30, 35.3 %). For the entire cohort, 36 (25.4 %) patients required subsequent treatment. In the 32 responders, only 1 (3.1 %) patient required a subsequent treatment. In patients who discontinued TKI, 25 (44.6 %) with stable disease received subsequent treatment compared to 0 (0.0 %) of responders. CONCLUSION: This retrospective study represents the largest cohort of DT patients treated with sorafenib or pazopanib to date. Discontinuation of treatment in responders is safe. The optimal treatment duration in patients with stable disease remains to be defined.

Cell Therapy Transplant Canada (CTTC) Consensus-Based Guideline 2024 for Management and Treatment of Chronic Graft-Versus-Host Disease and Future Directions for Development.

This is a consensus-based Canadian guideline whose primary purpose is to standardize and facilitate the management of chronic graft-versus-host disease (cGvHD) across the country. Creating uniform healthcare guidance in Canada is a challenge for a number of reasons including the differences in healthcare authority structure, funding and access to healthcare resources between provinces and territories, as well as the geographic size. These differences can lead to variable and unequal access to effective therapies for GvHD. This document will provide comprehensive and practical guidance that can be applied across Canada by healthcare professionals caring for patients with cGvHD. Hopefully, this guideline, based on input from GvHD treaters across the country, will aid in standardizing cGvHD care and facilitate access to much-needed novel therapies. This consensus paper aims to discuss the optimal approach to the initial assessment of cGvHD, review the severity scoring and global grading system, discuss systemic and topical treatments, as well as supportive therapies, and propose a therapeutic algorithm for frontline and subsequent lines of cGvHD treatment in adults and pediatric patients. Finally, we will make suggestions about the future direction of cGvHD treatment development such as (1) a mode-of-action-based cGvHD drug selection, according to the pathogenesis of cGvHD, (2) a combination strategy with the introduction of newer targeted drugs, (3) a steroid-free regimen, particularly for front line therapy for cGvHD treatment, and (4) a pre-emptive approach which can prevent the progression of cGvHD in high-risk patients destined to develop severe and highly morbid forms of cGvHD.

Real-world experience with ruxolitinib therapy for steroid-refractory acute graft versus host disease.

Acute graft versus host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplant (HCT) and is associated with significant morbidity and mortality. Steroid refractory aGVHD (SR-aGVHD) carries a particularly grim prognosis. Ruxolitinib has shown promise for treatment of SR-aGVHD in a phase 3 trial; however, safety and efficacy data outside of the clinical trial setting is lacking. We performed a multicenter retrospective study to examine the response to ruxolitinib and its efficacy in patients with SR-aGVHD. We included 59 patients treated with ruxolitinib for SR-aGVHD between 2015 and 2022. Of these 59 patients, 36 patients (61.0%) achieved a complete (CR) or partial response (PR) at 28 days, while 31 patients (52.5%) obtained a CR/PR at day 56. Patients that achieved a CR or PR at day 28 had a higher rate of overall survival (OS; 69.2%), compared with patients that did not (31.6%; p = 0.037). OS at 12 months was 41.5%, with a median OS duration of 5.3 months. Failure free survival (FFS) at 12 months was 29.1%, with a median FFS of 2.6 months. Overall, this real-world experience data support ruxolitinib as the standard of care for SR-aGVHD in a non-controlled trial population.

Adherence to CONSORT Guidelines and Reporting of the Determinants of External Validity in Clinical Oncology Randomized Controlled Trials: A Review of Trials Published in Four Major Journals between 2013 and 2015.

Our primary objective was to determine the proportion of trials that report the number of patients assessed for eligibility before randomization. We performed the systematic retrieval and analysis of all phase II, III, and IV RCTs published between 2013 and 2015 in four high-impact-factor journals in the field of clinical oncology. Among 456 RCTs reviewed, 236 trials (51.8%) reported the number of patients assessed for eligibility. Among the 236 trials that reported the entire enrollment process, the reasons for patient exclusion could be found in 184 trials (78%). A flow diagram was presented in 452 trials (99.1%), and 98 trials (21.5%) included a discussion on generalizability. Reporting the parameters of external validity in medical oncology RCTs is challenging. Improving adherence to the 2010 CONSORT guidelines concerning the enrollment process could help clinicians and health policymakers establish to whom trial results apply.

An Urgent Call to Integrate the Health Sector into the Post-2020 Global Biodiversity Framework.

There is a rapidly closing window of opportunity to stop biodiversity loss and secure the resilience of all life on Earth. In December 2022, Parties to the United Nations (UN) Convention on Biological Diversity (CBD) will meet in Montreal, Canada, to finalize the language and terms of the Post-2020 Global Biodiversity Framework (Post-2020 GBF). The Post-2020 GBF aims to address the shortcomings of the previous Strategic Plan on Biodiversity 2011-2020, by introducing a Theory of Change, that states that biodiversity protection will only be successful if unprecedented, transformative changes are implemented effectively by Parties to the CBD. In this policy perspective, we explore the implications of the Theory of Change chosen to underpin the Post-2020 GBF, specifically that broad social transformation is an outcome that requires actors to be specified. We detail how the health sector is uniquely positioned to be an effective actor and ally in support of the implementation of the Post-2020 GBF. Specifically, we highlight how the core competencies and financial and human resources available in the health sector (including unique knowledge, skill sets, experiences, and established trust) provide a compelling, yet mostly untapped opportunity to help create and sustain the enabling conditions necessary to achieve the goals and targets of the framework. While by no means a panacea for the world's biodiversity problems, we posit that explicitly omitting the health sector from the Post-2020 GBF substantially weakens the global, collective effort to catalyze the transformative changes required to safeguard biodiversity.

CAR T-Cells for the Treatment of Refractory or Relapsed Large B-Cell Lymphoma: A Single-Center Retrospective Canadian Study.

BACKGROUND: Chimeric antigen receptor (CAR) T-cells are an important new third-line treatment option for large B-cell lymphoma (LBCL). The objective response rates in pivotal early phase clinical trials with CAR T-cells were very promising. The objective of this study was to describe the efficacy results obtained with CAR T-cells infusions in our institution and to compare the toxicities of our cohort with those of pivotal trials and studies conducted in a real-life setting. PATIENTS AND METHODS: Efficacy and safety data were retrospectively collected from 25 patients with LBCL treated with CAR T-cells therapy at CHU de Québec-Université Laval. A literature search was then performed to identify other efficacy or safety data from a real-life setting. RESULTS: At 3 months post infusion, the objective response rate (ORR) in our population with tisagenlecleucel and axicabtagene-ciloleucel were 20% and 47%, respectively. Bulky disease was the only negative predictor of poor response at 3 months (0% vs. 53%, P = .03). Bulky disease was associated with a median PFS of 2 months compared to 5 months for non-bulky disease (P = .0009). Grade ≥ 3 hematological toxicities were greater in patients treated with axi-cel (60% vs. 20%, P = .048), without bone marrow involvement (55% vs. 0%, P =.046), without stage IV disease (72% vs. 21%, P =.02), with refractory disease (67% vs. 10%, P =.01) or having been affected by cytokine release syndrome (58% vs. 0%, P =.02). CONCLUSION: The poor response rate at 3 months after infusion in our cohort was influenced mainly by bulky disease. Further studies are needed to better characterize the loss of efficacy of CAR T-cells because the majority of patients will relapse over time.

Cost-Effectiveness of Brexucabtagene Autoleucel versus Best Supportive Care for the Treatment of Relapsed/Refractory Mantle Cell Lymphoma following Treatment with a Bruton's Tyrosine Kinase Inhibitor in Canada.

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.

Outcomes after delayed and second autologous stem cell transplant in patients with relapsed multiple myeloma.

We evaluated the outcomes of 168 patients undergoing delayed or second autologous stem cell transplant (ASCT) for relapsed multiple myeloma (MM) from 2010 to 2019. Overall, 21% (n = 35) patients had received a prior transplant and 69% (n = 116) underwent transplant at first relapse. Overall, 27% patients had high-risk cytogenetics and 15% had ISS stage III disease. Stem cell collection was performed after relapse in 72% and 35% of patients received maintenance therapy. Median PFS from salvage treatment and transplant were 28 and 19 months, respectively. Median OS from salvage treatment and transplant was 69 and 55 months. Multivariate analysis revealed that ASCT in first relapse was associated with superior PFS (HR 0.63, p = 0.03) and OS (HR 0.59, p = 0.04) compared to later lines of therapy. In addition, PFS of ≥36 months with prior therapy was associated with improved PFS (HR 0.62, p = 0.04) and OS (HR 0.41, p = 0.01). Ninety-five patients underwent delayed transplant at first relapse, median PFS and OS from start of therapy was 30 and 69 months, and median OS from diagnosis was 106 months. These data may serve as a guide when counseling patients undergoing ASCT for relapsed MM and provide a benchmark in designing clinical trials of transplantation/comparative treatments for relapsed MM.

Outcomes with autologous stem cell transplant vs. non-transplant therapy in patients 70 years and older with multiple myeloma.

We evaluated 79 patients with multiple myeloma (MM) ≥70 years referred to our blood and marrow transplant clinic, within 1 year of diagnosis from 2010 to 2019, for consideration of autologous stem cell transplant (ASCT). Thirty-eight (48%) of 79 patients underwent ASCT. ASCT was not pursued in 41 (52%) patients due to: patient or physician preference in 80% (n = 33) or ineligibility in 20% (n = 8). Baseline characteristics of patients in the two groups were similar. Median PFS from treatment start amongst patients undergoing ASCT (n = 38) vs. not (n = 41) was 41 months vs. 33 months, p = 0.03. There was no difference in OS, with estimated 5-year OS of 73% vs. 83%, respectively (p = 0.86). Day +100 transplant-related mortality (TRM) was 0%. ASCT was an independent favorable prognostic factor for PFS in multivariate analysis, after accounting for HCT-CI score, performance status, hematologic response, and maintenance. Finally, patients ≥70 years undergoing ASCT had similar PFS compared to a contemporaneous institutional cohort of patients <70 years (n = 631) (median PFS from transplant: 36 vs. 47 months, p = 0.25). In this retrospective analysis, ASCT was associated with low TRM and better PFS in fit older adults with MM compared to non-transplant therapy, with comparable benefits as seen in younger patients.

Outcomes with Autologous or Allogeneic Stem Cell Transplantation in Patients with Plasma Cell Leukemia in the Era of Novel Agents.

Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell disorder. The optimal treatment approach, including whether to pursue an autologous (auto) or allogeneic (allo) stem cell transplantation (SCT) is not clear, given the lack of clinical trial-based evidence. This single-center retrospective study describes the outcomes of 16 patients with PCL (n = 14 with primary PCL) who underwent either autoSCT (n = 9) or alloSCT (n = 7) for PCL in the era of novel agents, between 2007 and 2019. The median age of the cohort was 58 years. High-risk cytogenetics were found in 50% of the patients. All patients received a proteasome inhibitor and/or immunomodulatory drug-based regimen before transplantation. At the time of transplantation, 10 patients (62%) obtained at least a very good partial response (VGPR). The response after autoSCT (3 months) was at least a VGPR in 6 patients (67%; complete response [CR] in 5). All patients undergoing alloSCT achieved a CR at 3 months. Maintenance therapy was provided to 5 patients (56%) after autoSCT. The median progression-free survival after transplantation was 6 months in the autoSCT group, compared with 18 months in the alloSCT group (P = .09), and median overall survival (OS) after transplantation in the 2 groups was 19 months and 40 months, respectively (P = .41). The median OS from diagnosis was 27 months and 49 months, respectively (P = .50). Of the 11 deaths, 10 patients (91%) died of relapsed disease. AlloSCT was not observed to offer any significant survival advantage over autoSCT in PCL, in agreement with recent reports, and relapse remains the primary cause of death in these patients.

Evaluation of the Impact of Autologous Hematopoietic Stem Cell Transplantation on the Quality of Life of Older Patients with Lymphoma.

High-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplantation (AHSCT) improves survival in patients with chemosensitive non-Hodgkin lymphoma (NHL). Determination of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) has contributed to improve patient selection while allowing for prediction of nonrelapse mortality. We previously demonstrated the efficacy and safety of AHSCT in a cohort of older patients with chemosensitive NHL. Quality of life following AHSCT still has not been widely evaluated. The goal of this study was to assess the long-term quality of life of elderly patients surviving AHSCT. This single-center, Research and Ethics Committee-approved study investigated QoL in survivors of AHSCT for the treatment of NHL in a cohort of older patients. Inclusion criteria were defined as patients age ≥60 years who underwent AHSCT for NHL between January 1, 2008, and January 1, 2015, at our center. Fifty-nine patients from the original cohort of 90 survived at a median of 50 months post-AHSCT. Forty-seven (79.7%) of those patients agreed to complete the QoL assessment questionnaires after the transplantation and are included in this report. All patients provided signed informed consent. We used the EQ-5D instrument to assess mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire to assess physical, social/family, emotional, and functional well-being and BMT-specific concerns. With both tools, a higher score indicates better QoL. Fifteen percent of patients were in relapse at the time of the QoL assessment. In the EQ-5D, few patients (9%) reported severe impairment, which requires significant negative effects in 4 or 5 domains. Lower Karnofsky Performance Status (KPS) score at the time of transplantation was negatively correlated with mobility (P= .001), self-care (P= .001), and usual activities (P= .007) dysfunction. Anxiety was significant for patients in relapsed after transplantation (P= .002). FACT-BMT questionnaire results demonstrated that physical, social, and emotional well-being were all well preserved after the transplantation, whereas functional well-being was more variable among patients. Relapse was associated with impaired functional well-being (P= .007) and lower total FACT-BMT score (P= .014). Other comparators, including the conditioning regimen, sex, age subgroups (<65 or ≥65 years), HCT-CI score, and disease status at transplantation, did not impact any of these outcomes. This study demonstrates that physical, social, and functional well-being are preserved in older patients following AHSCT. Low KPS score before AHSCT is a predictor of disability at distance from AHSCT. Relapse following AHSCT remains the most significant impediment to maintaining a good QoL. Innovative interventions to improve performance status before transplantation and measures to prevent relapse thereafter should be investigated to improve survival and QoL.

Outcome of autologous hematopoietic stem cell transplant in older patients with B cell lymphoma when selected for fitness and chemosensitive disease.

BACKGROUND: Autologous hematopoietic stem cell transplantation (AHSCT) in the older population is associated with an increased risk of morbidity and mortality. Determination of the hematopoietic cell transplant comorbidity index (HCT-CI) has contributed to improve patient selection while allowing prediction of their non-relapse mortality (NRM). The goal of this study was to identify factors influencing both safety and efficacy of AHSCT in an older non-Hodgkin lymphoma (NHL) population to better select those who will benefit from this intervention in the Canadian context of a single-payer government healthcare program. METHODS: This single center, retrospective study, examined clinical outcomes in 90 consecutive older patients (≥60 years old) with B-cell NHL treated with AHSCT between 2008 and 2014. FINDINGS: Median age was 63 (60-69) at time of transplantation. The HCT-CI risk score was low, intermediate and high in 34%, 40% and 26% of patients, respectively. NRM was 1% at 100 days and one-year post transplant and not influenced by age. At a median follow-up of 52 months, median progression-free survival (PFS) was 56 months while median overall survival (OS) was still not reached. Stable and progressive disease status at time of transplantation were associated with a lower PFS (HR 2.94) and OS (HR 3.91). BEAC conditioning and a graft cell dose 5 × 106 CD34+/kg led to faster recovery, decreased toxicity and resource consumption. INTERPRETATION: In the older population, AHSCT is safe and optimal when restricted to fit chemosensitive patients.

Tracking human activity and well-being in natural environments using wearable sensors and experience sampling.

A growing range of studies have begun to document the health and well-being benefits associated with contact with nature. Most studies rely on generalized self-reports following engagement in the natural environment. The actual in-situ experience during contact with nature, and the environmental features and factors that evoke health benefits have remained relatively unexplored. Smartphones offer a new opportunity to monitor and interact with human subjects during everyday life using techniques such as Experience Sampling Methods (ESM) that involve repeated self-reports of experiences as they occur in-situ. Additionally, embedded sensors in smartphones such as Global Positioning Systems (GPS) and accelerometers can accurately trace human activities. This paper explores how these techniques can be combined to comprehensively explore the perceived health and well-being impacts of contact with nature. Custom software was developed to passively track GPS and accelerometer data, and actively prompt subjects to complete an ESM survey at regular intervals throughout their visit to a provincial park in Ontario, Canada. The ESM survey includes nine scale questions concerning moods and emotions, followed by a series of open-ended experiential questions that subjects provide recorded audio responses to. Pilot test results are used to illustrate the nature, quantity and quality of data obtained. Participant activities were clearly evident from GPS maps, including especially walking, cycling and sedate activities. From the ESM surveys, participants reported an average of 25 words per question, taking an average of 15 s to record them. Further qualitative analysis revealed that participants were willing to provide considerable insights into their experiences and perceived health impacts. The combination of passive and interactive techniques is sure to make larger studies of this type more affordable and less burdensome in the future, further enhancing the ability to understand how contact with nature enhances health and well-being.

Natural resource manager perceptions of agency performance on climate change.

An important precursor to the adoption of climate change adaptation strategies is to understand the perceived capacity to implement and operationalize such strategies. Utilizing an importance-performance analysis (IPA) evaluation framework, this article presents a comparative case study of federal and state land and natural resource manager perceptions of agency performance on factors influencing adaptive capacity in two U.S. regions (northern Colorado and southwestern South Dakota). Results revealed several important findings with substantial management implications. First, none of the managers ranked the adaptive capacity factors as a low priority. Second, managers held the perception that their agencies were performing either neutrally or poorly on most factors influencing adaptive capacity. Third, gap analysis revealed that significant improvements are required to facilitate optimal agency functioning when dealing with climate change-related management issues. Overall, results suggest that a host of institutional and policy-oriented (e.g., lack of clear mandate to adapt to climate change), financial and human resource (e.g., inadequate staff and financial resources), informational (e.g., inadequate research and monitoring programs) and contextual barriers (e.g., sufficient regional networks to mitigate potential transboundary impacts) currently challenge the efficient and effective integration of climate change into decision-making and management within agencies working in these regions. The IPA framework proved to be an effective tool to help managers identify and understand agency strengths, areas of concern, redundancies, and areas that warrant the use of limited funds and/or resource re-allocation in order to enhance adaptive capacity and maximize management effectiveness with respect to climate change.

Changing climate, challenging choices: identifying and evaluating climate change adaptation options for protected areas management in Ontario, Canada.

Climate change will pose increasingly significant challenges to managers of parks and other forms of protected areas around the world. Over the past two decades, numerous scientific publications have identified potential adaptations, but their suitability from legal, policy, financial, internal capacity, and other management perspectives has not been evaluated for any protected area agency or organization. In this study, a panel of protected area experts applied a Policy Delphi methodology to identify and evaluate climate change adaptation options across the primary management areas of a protected area agency in Canada. The panel identified and evaluated one hundred and sixty five (165) adaptation options for their perceived desirability and feasibility. While the results revealed a high level of agreement with respect to the desirability of adaptation options and a moderate level of capacity pertaining to policy formulation and management direction, a perception of low capacity for implementation in most other program areas was identified. A separate panel of senior park agency decision-makers used a multiple criterion decision-facilitation matrix to further evaluate the institutional feasibility of the 56 most desirable adaptation options identified by the initial expert panel and to prioritize them for consideration in a climate change action plan. Critically, only two of the 56 adaptation options evaluated by senior decision-makers were deemed definitely implementable, due largely to fiscal and internal capacity limitations. These challenges are common to protected area agencies in developed countries and pervade those in developing countries, revealing that limited adaptive capacity represents a substantive barrier to biodiversity conservation and other protected area management objectives in an era of rapid climate change.