Developing enhanced immunotherapy using NKG2A knockout human pluripotent stem cell-derived NK cells.

Cancer immunotherapy is gaining increasing attention. However, immune checkpoints are exploited by cancer cells to evade anti-tumor immunotherapy. Here, we knocked out NKG2A, an immune checkpoint expressed on natural killer (NK) cells, in human pluripotent stem cells (hPSCs) and differentiated these hPSCs into NK (PSC-NK) cells. We show that NKG2A knockout (KO) enhances the anti-tumor and anti-viral capabilities of PSC-NK cells. NKG2A KO endows PSC-NK cells with higher cytotoxicity against HLA-E-expressing glioblastoma (GBM) cells, leukemia cells, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected cells in vitro. The NKG2A KO PSC-NK cells also exerted potent anti-tumor activity in vivo, leading to substantially suppressed tumor progression and prolonged survival of tumor-bearing mice in a xenograft GBM mouse model. These findings underscore the potential of PSC-NK cells with immune checkpoint KO as a promising cell-based immunotherapy. The unlimited supply and ease of genetic engineering of hPSCs makes genetically engineered PSC-NK an attractive option for easily accessible "off-the-shelf" cancer immunotherapy.

New insights into the biology of T-cell lymphomas.

ABSTRACT: Peripheral T-cell lymphomas (PTCLs) encompass a heterogeneous group of postthymic T-cell lymphomas with >30 distinct subtypes associated with varied clinicopathological features. Unfortunately, the overall survival of the major PTCL subtypes is dismal and has not improved for decades; thus, there is an urgent unmet clinical need to improve diagnosis, therapies, and clinical outcomes. The diagnosis is often challenging, requiring a combinatorial evaluation of clinical, morphologic, and immunophenotypic features. PTCL pathobiology is difficult to investigate due to enormous intertumor and intratumor heterogeneity, limited tissue availability, and the paucity of authentic T-cell lymphoma cell lines or genetically faithful animal models. The application of transcriptomic profiling and genomic sequencing has markedly accelerated the discovery of new biomarkers, molecular signatures, and genetic lesions, and some of the discoveries have been included in the revised World Health Organization or International Consensus Classification. Genome-wide investigations have revealed the mutational landscape and transcriptomic profiles of PTCL entities, defined the cell of origin as a major determinant of T-cell lymphoma biology, and allowed for the refinement of biologically and clinically meaningful entities for precision therapy. In this review, we prioritize the discussion on common nodal PTCL subtypes together with 2 virus-associated T-cell and natural killer cell lymphomas. We succinctly review normal T-cell development, differentiation, and T-cell receptor signaling as they relate to PTCL pathogenesis and biology. This review will facilitate a better biological understanding of the different PTCL entities and their stratification for additional studies and target-directed clinical trials.

The impact of perioperative transfusions on the oncologic outcomes of patients with ovarian cancer: A population-based study.

Perioperative blood transfusion in ovarian cancer patients was associated with a 28% increase in all-cause mortality. The negative impact of perioperative blood transfusion extends beyond the immediate postoperative period. OBJECTIVES: The effect of perioperative blood transfusions on long-term oncologic outcomes of patients with advanced ovarian cancer undergoing cytoreductive surgery remains uncertain. Our study aims to determine the association between perioperative blood transfusion and all-cause mortality in this population. METHODS: Using province-wide administrative databases, patients with advanced ovarian cancer who underwent surgery between 2007 and 2021 as part of first-line treatment were identified. Perioperative transfusion was defined as any transfusion from date of surgery to discharge from hospital. Multivariable Cox proportional hazards regression models were used to determine if there was an independent association of transfusion with all-cause mortality, accounting significant confounders. RESULTS: A total of 5891 patients had cytoreductive surgery for advanced ovarian cancer between 2007 and 2021, of which 2898 (49.2%) had interval cytoreductive surgery (ICS) and 2993 (50.8%) had primary cytoreductive surgery (PCS). Perioperative blood transfusion was given to 37.3% of patients (40.5% ICS and 34.2% PCS). On multivariable analysis, there was an increased hazard of all-cause mortality for patients receiving perioperative transfusion compared to those who did not (hazard ratio: 1.28; 95% CI: 1.20-1.37). The association of increased all-cause mortality was observed starting 1 year after surgery, was sustained thereafter, and seen in both ICS and PCS groups. CONCLUSION: Perioperative blood transfusion after cytoreductive surgery for ovarian cancer is common in Ontario, Canada and was significantly associated with an increase in all-cause mortality. Blood transfusion is a poor prognostic factor, and the negative impact of blood transfusion persists beyond the immediate postoperative period.

Co-shared genomic alterations within tumors from patients with both myeloproliferative neoplasms and lymphoma.

Not available.

MGA deletion leads to Richter's transformation by modulating mitochondrial OXPHOS.

Richter's transformation (RT) is a progression of chronic lymphocytic leukemia (CLL) to aggressive lymphoma. MGA (Max gene associated), a functional MYC suppressor, is mutated at 3% in CLL and 36% in RT. However, genetic models and molecular mechanisms of MGA deletion that drive CLL to RT remain elusive. We established an RT mouse model by knockout of Mga in the Sf3b1/Mdr CLL model using CRISPR-Cas9 to determine the role of Mga in RT. Murine RT cells exhibited mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). Through RNA sequencing and functional characterization, we identified Nme1 (nucleoside diphosphate kinase) as an Mga target, which drives RT by modulating OXPHOS. Given that NME1 is also a known MYC target without targetable compounds, we found that concurrent inhibition of MYC and electron transport chain complex II substantially prolongs the survival of RT mice in vivo. Our results suggest that the Mga-Nme1 axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a potential therapeutic avenue for RT.

MiR-17∼92 is involved in NF-κB activation via targeting the ubiquitin-editing proteins to mediate RIP1 complex polyubiquitinations in ABC-DLBCL.

Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive lymphoma characterized by constitutive NF-κB activation, but whether miR-17∼92 contributes to this activation remains unclear. Herein, we sought to evaluate the role of miR-17∼92 in the process of NF-κB activation in ABC-DLBCL. We found that the expression of miR-17∼92 primary transcript was positively correlated with NF-κB activity, miR-17∼92 activated the NF-κB signaling in ABC-DLBCL, and its over-expression promoted ABC-DLBCL cell growth, accelerated cell G1 to S phase transition and enhanced cell resistance to NF-κB inhibitor. Importantly, miR-17∼92 promoted NF-κB activation through directly targeting multiple ubiquitin-editing regulators to lead to increase the K63-linked polyubiquitination and decrease the K48-linked polyubiquitination of RIP1 complex in ABC-DLBCL. We further found that miR-17∼92 selectively activated IκB-α and NF-κB p65 but not NF-κB p52/p100, and high miR-17∼92 expression was also associated with poorer outcome in ABC-DLBCL patients. Overall, our results showed that miR-17∼92 selectively activated the canonical NF-κB signaling via targeting ubiquitin-editing regulators to lead to constitutively NF-κB activation and poorer outcome in ABC-DLBCL. These findings uncovered an innovative function of miR-17∼92 and previously unappreciated regulatory mechanism of NF-κB activation in ABC-DLBCL. Targeting miR-17∼92 may thus provide a novel bio-therapeutic strategy for ABC-DLBCL patients.

A population-based analysis of the management of symptoms of depression among patients with stage IV non-small cell lung cancer (NSCLC) in Ontario, Canada.

PURPOSE: Patients with lung cancer can experience significant psychological morbidities including depression. We characterize patterns and factors associated with interventions for symptoms of depression in stage IV non-small cell lung cancer (NSCLC). METHODS: We conducted a population-based cohort study using health services administrative data in Ontario, Canada of stage IV NSCLC diagnosed from January 2007 to September 2018. A positive symptom of depression score was defined by reporting at least one ESAS (Edmonton Symptom Assessment System) depression score ≥ 2 following diagnosis until the end of follow-up (September 2019). Patient factors included age, sex, comorbidity burden, rurality of residence, and neighbourhood income quintile. Interventions included psychiatry assessment, psychology referral, social work referral and anti-depressant medical therapy (for patients ≥ 65 years with universal drug coverage). Multivariable modified Poisson regression models were used to examine the association between patient factors and intervention use for patients who reported symptoms of depression. RESULTS: In the cohort of 13,159 patients with stage IV NSCLC lung cancer, symptoms of depression were prevalent (71.4%, n = 9,397). Patients who reported symptoms of depression were more likely to receive psychiatry assessment/psychology referral (7.8% vs 3.5%; SD [standardized difference] 0.19), social work referral (17.4% vs 11.9%; SD 0.16) and anti-depressant prescriptions (23.8% vs 13.8%; SD 0.26) when compared to patients who did not report symptoms of depression respectively. In multivariable analyses, older patients were less likely to receive any intervention. Females were more likely to obtain a psychiatry assessment/psychology referral or social work referral. In addition, patients from non-major urban or rural residences were less likely to receive psychiatry assessment/psychology referral or social work referral, however patients from rural residences were more likely to be prescribed anti-depressants. CONCLUSIONS: There is high prevalence of symptoms of depression in stage IV NSCLC. We identify patient populations, including older patients and rural patients, who are less likely to receive interventions that will help identifying and screening for symptoms of depression.

Motive and opportunity: MYC rearrangements in high-grade B-cell lymphoma with MYC and BCL2 rearrangements (an LLMPP study).

ABSTRACT: Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double hit"; HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of and mechanisms driving IG vs non-IG MYC rearrangements have not been elucidated. Here, we used custom targeted capture and/or whole-genome sequencing to characterize oncogene rearrangements across 883 mature B-cell lymphomas including Burkitt lymphoma, follicular lymphoma, DLBCL, and HGBCL-DH-BCL2 tumors. We demonstrate that, although BCL2 rearrangement topology is consistent across entities, HGBCL-DH-BCL2 have distinct MYC rearrangement architecture relative to tumors with single MYC rearrangements or with both MYC and BCL6 rearrangements (HGBCL-DH-BCL6), including both a higher frequency of non-IG rearrangements and different architecture of MYC::IGH rearrangements. The distinct MYC rearrangement patterns in HGBCL-DH-BCL2 occur on the background of high levels of somatic hypermutation across MYC partner loci in HGBCL-DH-BCL2, creating more opportunity to form these rearrangements. Furthermore, because 1 IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B-cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.

Association between anaesthesia-surgery team sex diversity and major morbidity.

BACKGROUND: Team diversity is recognized not only as an equity issue but also a catalyst for improved performance through diversity in knowledge and practices. However, team diversity data in healthcare are limited and it is not known whether it may affect outcomes in surgery. This study examined the association between anaesthesia-surgery team sex diversity and postoperative outcomes. METHODS: This was a population-based retrospective cohort study of adults undergoing major inpatient procedures between 2009 and 2019. The exposure was the hospital percentage of female anaesthetists and surgeons in the year of surgery. The outcome was 90-day major morbidity. Restricted cubic splines were used to identify a clinically meaningful dichotomization of team sex diversity, with over 35% female anaesthetists and surgeons representing higher diversity. The association with outcomes was examined using multivariable logistic regression. RESULTS: Of 709 899 index operations performed at 88 hospitals, 90-day major morbidity occurred in 14.4%. The median proportion of female anaesthetists and surgeons was 28 (interquartile range 25-31)% per hospital per year. Care in hospitals with higher sex diversity (over 35% female) was associated with reduced odds of 90-day major morbidity (OR 0.97, 95% c.i. 0.95 to 0.99; P = 0.02) after adjustment. The magnitude of this association was greater for patients treated by female anaesthetists (OR 0.92, 0.88 to 0.97; P = 0.002) and female surgeons (OR 0.83, 0.76 to 0.90; P < 0.001). CONCLUSION: Care in hospitals with greater anaesthesia-surgery team sex diversity was associated with better postoperative outcomes. Care in a hospital reaching a critical mass with over 35% female anaesthetists and surgeons, representing higher team sex-diversity, was associated with a 3% lower odds of 90-day major morbidity.

Risk of Cesarean Delivery Among People With Inflammatory Bowel Disease According to Disease Characteristics: A Population-Based Study.

OBJECTIVES: It is unclear if use of cesarean delivery in people with inflammatory bowel disease (IBD) is guideline-concordant. We compared the odds of cesarean delivery among primiparous individuals with IBD versus without, overall, and by disease characteristics, as well as time to subsequent delivery. METHODS: Retrospective matched population-based cohort study between 1 April 1994 and 31 March 2020. Primiparous individuals aged 15-55 years with IBD were matched to those without IBD on age, year, hospital, and number of newborns delivered. Primary outcome was cesarean delivery versus vaginal delivery. Multivariable conditional logistic regression analyses were performed to estimate the odds of cesarean delivery among individuals with and without IBD as a binary exposure, and a categorical exposure based on IBD-related indications for cesarean delivery. Time to subsequent delivery was evaluated using a Cox proportional hazard model. RESULTS: We matched 7472 individuals with IBD to 37 360 individuals without (99.02% match rate). Individuals with IBD were categorised as having perianal (PA) disease (IBD-PA, n = 764, 10.2%), prior ileal pouch-anal anastomosis (n = 212, 2.8%), or IBD-Other (n = 6496, 86.9%). Cesarean delivery rates were 35.4% in the IBD group versus 30.4% in their controls (adjusted odds ratio 1.27; 95% CI 1.20-1.34). IBD-ileal pouch-anal anastomosis had a cesarean delivery rate of 66.5%, compared to 49.9% in IBD-PA and 32.7% in IBD-Other. There was no significant difference in the rate of subsequent delivery in those with and without IBD (adjusted hazard ratio 1.03; 95% CI 1-1.07). CONCLUSIONS: The higher risk of cesarean delivery in people with IBD reflects guideline-concordant use. Individuals with and without IBD were equally likely to have a subsequent delivery with similar timing.

MYC overexpression in natural killer cell lymphoma: prognostic and therapeutic implications.

The current clinical management of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the prognostic index of NK cells lymphoma with Epstein-Barr virus (PINK-E) prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA sequencing used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-sequencing data upon MYC knockdown with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression.

Pharmacological profiling of a berbamine derivative for lymphoma treatment.

ABSTRACT: Ca2+/calmodulin-dependent protein kinase II γ (CAMKIIγ) has been identified as a potential target for treating cancer. Based on our previous study of berbamine (BBM) as a CAMKIIγ inhibitor, we have synthesized a new BBM derivative termed PA4. Compared with BBM, PA4 showed improved potency and specificity and was more cytotoxic against lymphoma and leukemia than against other types of cancer. In addition to indirectly targeting c-Myc protein stability, we demonstrated that its cytotoxic effects were also mediated via increased reactive oxygen species production in lymphoma cells. PA4 significantly impeded tumor growth in vivo in a xenograft T-cell lymphoma mouse model. Pharmacokinetics studies demonstrated quick absorption into plasma after oral administration, with a maximum concentration of 1680 ± 479 ng/mL at 5.33 ± 2.31 hours. The calculated oral absolute bioavailability was 34.1%. Toxicity assessment of PA4 showed that the therapeutic window used in our experiments was safe for future development. Given its efficacy, safety, and favorable pharmacokinetic profile, PA4 is a potential lead candidate for treating lymphoma.

TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)-histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63-rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.

Access to symptom screening and severe symptom risk among cancer patients with major mental illness.

INTRODUCTION: Cancer symptom screening has the potential to improve cancer outcomes, including reducing symptom burden among patients with major mental illness (MMI). We determined rates of symptom screening with the Edmonton Symptom Assessment System (ESAS-r) and risk of severe symptoms in cancer patients with MMI. METHODS: This retrospective cohort study used linked administrative health databases of adults diagnosed with cancer between 2007 and 2020. An MMI was measured in the 5 years prior to cancer diagnosis and categorized as inpatient, outpatient, or no MMI. Outcomes were defined as time to first ESAS-r screening and time to first moderate-to-severe symptom score. Cause-specific and Fine and Gray competing events models were used for both outcomes, controlling for age, sex, rural residence, year of diagnosis and cancer site. RESULTS: Of 389,870 cancer patients, 4049 (1.0%) had an inpatient MMI and 9775 (2.5%) had an outpatient MMI. Individuals with inpatient MMI were least likely to complete an ESAS-r (67.5%) compared to those with outpatient MMI (72.3%) and without MMI (74.8%). Compared to those without MMI, individuals with an inpatient or outpatient MMI had a lower incidence of symptom screening records after accounting for the competing risk of death (subdistribution Hazard Ratio 0.77 (95% CI 0.74-0.80) and 0.88 (95% CI 0.86-0.90) respectively). Individuals with inpatient and outpatient MMI status consistently had a significantly higher risk of reporting high symptom scores across all symptoms. CONCLUSIONS: Understanding the disparity in ESAS-r screening and management for cancer patients with MMI is a vital step toward providing equitable cancer care.

Prevalence of frailty and its association with clinical outcomes in myeloproliferative neoplasms: a population-based study.

Clinical implications of frailty in myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are unknown. In this population-based study, all incident cases of MPN from the Ontario cancer registry between 2004 and 2019 (N = 10 336; ET = 5108; PV = 3843; MF = 1385) and their matched controls (for age, sex, residence, and income) in a 1:4 ratio were included. Baseline frailty measured using the Johns Hopkins Adjusted Clinical Groups frailty indicator and McIsaac frailty index (mFI), categorized as fit, prefrail, or frail if mFI <0.10, 0.11 to 0.20, >0.20), was significantly higher in ET, PV, and MF compared with matched controls (standardized mean difference of 0.27, 0.27, and 0.28). Over 23%, 20%, and 34% of patients with ET, PV, and MF were frail or prefrail despite a younger age (<65 years) or minimal comorbidities. In Cox proportional regression, frailty was independently associated with worse overall survival (OS) after adjusting for age, sex, and comorbidities compared with mFI-fit patients. The hazard ratios (95% confidence interval) for OS for mFI-prefrail and mFI-frail patients were: 1.6 (1.3-1.9) and 3.6 (2.9-4.4) in ET, 1.3 (1.1-1.5) and 2.7 (2.1-3.4) in PV, and 1.2 (1.0-1.5) and 2.0 (1.5-2.7) in MF. Patients with MPN have a substantially higher prevalence of frailty compared with matched controls, which is associated with reduced OS, independent of age or comorbidities.

The impact of unexpected intensive care unit admission after cancer surgery on long-term symptom burden among older adults: a population-based longitudinal analysis.

BACKGROUND: Older adults are at high-risk for a post-operative intensive care unit (ICU) admission, yet little is known about the impact of these admissions on quality of life. The objective of this study was to evaluate the impact of an unexpected post-operative ICU admission on the burden of cancer symptoms among older adults who underwent high-intensity cancer surgery and survived to hospital discharge. METHODS: We performed a population-based cohort study of older adults (age ≥ 70) who underwent high-intensity cancer surgery and survived to hospital discharge in Ontario, Canada (2007-2017). Using the Edmonton Symptom Assessment System (ESAS), a standardized tool that quantifies patient-reported physical, mental, and emotional symptoms, we described the burden of cancer symptoms during the year after surgery. Total symptom scores ≥ 40 indicated a moderate-to-severe symptom burden. Modified log-Poisson analysis was used to estimate the impact of an unexpected post-operative ICU admission (admission not related to routine monitoring) on the likelihood of experiencing a moderate-to-severe symptom burden during the year after surgery, accounting for potential confounders. We then used multivariable generalized linear mixed models to model symptom trajectories among patients with two or more ESAS assessments. A 10-point difference in total symptom scores was considered clinically significant. RESULTS: Among 16,560 patients (mean age 76.5 years; 43.4% female), 1,503 (9.1%) had an unexpected ICU admission. After accounting for baseline characteristics, patients with an unexcepted ICU admission were more likely to experience a moderate-to-severe symptom burden relative to those without an unexpected ICU admission (RR 1.64, 95% CI 1.31-2.05). Specifically, among patients with an unexcepted ICU admission the average probability of experiencing moderate-to-severe symptoms ranged from 6.9% (95 CI 5.8-8.3%) during the first month after surgery to 3.2% (95% CI 0.9-11.7%) at the end of the year. Among the 11,229 (67.8%) patients with multiple ESAS assessments, adjusted differences in total scores between patients with and without an unexpected ICU admission ranged from 2.0 to 5.7-points throughout the year (p < 0.001). CONCLUSION: While unexpected ICU admissions are associated with a small increase in the likelihood of experiencing a moderate-to-severe symptom burden, most patients do not experience a high overall symptom burden during the year after surgery. These findings support the role of aggressive therapy among older adults after major surgery.

The impact of a cancer diagnosis on nonfatal self-injury: a matched cohort study in Ontario.

BACKGROUND: Psychological distress following a cancer diagnosis potentially increases the risk of intentional, nonfatal self-injury. The purpose of this work is to evaluate and compare rates of nonfatal self-injury among individuals in Ontario diagnosed with cancer against matched controls with no history of cancer. METHODS: Adults in Ontario diagnosed with cancer from 2007 to 2019 were matched to 2 controls with no history of cancer, based on age and sex. We calculated the absolute and relative difference in rates of nonfatal self-injury in the 5 years before and after the index date (date of cancer diagnosis and dummy date for controls). We used crude difference-in-differences methods and adjusted Poisson regression-based analyses to examine whether the change in rates of nonfatal self-injury before and after index differed between cancer patients and controls. RESULTS: The cohort included 803 740 people with cancer and 1 607 480 matched controls. In the first year after diagnosis, individuals with cancer had a 1.17-fold increase in rates of nonfatal self-injury (95% confidence interval [CI] 1.03-1.33) compared with matched controls, after accounting for pre-existing differences in rates of nonfatal self-injury and other clinical characteristics between the groups. Rates of nonfatal self-injury remained elevated in the cancer group by 1.07-fold for up to 5 years after diagnosis (95% CI 0.95-1.21). INTERPRETATION: In this study, incidence of nonfatal self-injury was higher among individuals diagnosed with cancer, with the greatest impact observed in the first year after diagnosis. This work highlights the need for robust and accessible psychosocial oncology programs to support mental health along the cancer journey.

Dyspnea in patients with stage IV non-small cell lung cancer: a population-based analysis of disease burden and patterns of care.

Background: Patients with metastatic non-small cell lung cancer (NSCLC) experience significant morbidity with dyspnea being a common symptom with a prevalence of 70%. The objective of this study was to determine factors associated with a moderate-to-severe dyspnea score based on the Edmonton Symptom Assessment System (ESAS), as well as resultant patterns of intervention and factors correlated to intervention receipt. Methods: Using health services administrative data, we conducted a population-based study of all patients diagnosed with metastatic NSCLC treated from January 2007 to September 2018 in the province of Ontario. The primary outcomes of interest are the prevalence of moderate-to-severe dyspnea scores, and the receipt of dyspnea-directed intervention. Differences in baseline characteristic between moderate-to-severe dyspnea and low dyspnea score cohorts were assessed by comparative statistics. Predictors of intervention receipt for patients with moderate-to-severe dyspnea scores were estimated using multivariable modified Poisson regression. Results: The initial study cohort included 13,159 patients diagnosed with metastatic NSCLC and of these, 9,434 (71.7%) reported a moderate-to-severe dyspnea score. Compared to patients who did not report moderate-to-severe dyspnea scores, those who reported a moderate-to-severe dyspnea score were more likely to complete a greater number of ESAS surveys, be male, have a higher Elixhauser comorbidity index (ECI) score, and receive subsequent systemic therapy after diagnosis. Most patients with a moderate-to-severe dyspnea score received intervention (96%), of which the most common were palliative care management (87%), thoracic radiotherapy (56%) and thoracentesis (37%). Multivariable regression identified older patients to be less likely to undergo pleurodesis. Thoracentesis was less common for patients living in rural and non-major urban areas, lower income areas, and earlier year of diagnosis. Receipt of thoracic radiotherapy was less common for older patients, females, those with ECI ≥4, patients living in major urban areas, and those with later year of diagnosis. Finally, palliative care referrals were less frequent for patients with ECI ≥4, age 60-69, residence outside of major urban areas, earlier year of diagnosis, and lower income areas. Conclusions: Dyspnea is a prevalent symptom amongst patients with metastatic NSCLC. Subpopulations of patients with moderate-to-severe dyspnea scores were in which inequities may exist in access to care that require further attention and evaluation.

Pain and Interventions in Stage IV Non-Small Cell Lung Cancer: A Province-Wide Analysis.

Pain is a common symptom in stage IV non-small cell lung cancer (NSCLC). The objective of the study was to examine the use of interventions and factors associated with interventions for pain. A population-based cohort study in Ontario, Canada was conducted with patients diagnosed with stage IV NSCLC from January 2007 to September 2018. An Edmonton Symptom Assessment System (ESAS) score of ≥4 defined moderate-to-severe pain following diagnosis. The study cohort included 13,159 patients, of which 68.5% reported at least one moderate-to-severe pain score. Most patients were assessed by a palliative care team (85.4%), and the majority received radiation therapy (73.2%). The use of nerve block was rare (0.8%). For patients ≥65 years of age who had drug coverage, 59.6% received an opiate prescription. Patients with moderate-to-severe pain were more likely to receive palliative assessment or radiation therapy compared to patients with none or mild pain. Patients aged ≥70 years and with a greater comorbidity burden were associated with less likelihood to receive radiation therapy. Patients from rural/non-major urban residence and with a greater comorbidity burden were also less likely to receive palliative care assessment. Factors associated with interventions for pain are described to inform future symptom management in this population.