Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.

The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM(P37-V202)) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development, and our study illustrates the use of CAR-T cells as "micro-pharmacies" able to deliver an anti-cancer protein.

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.

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.

DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T cells in PTCL-NOS.

Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL-not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881-R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.

Genomic profiling for clinical decision making in lymphoid neoplasms.

With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee.

Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

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.

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

The current clinical management of Extranodal 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 PINK-E prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown (KD) in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA-sequencing (RNA-seq) 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-seq data upon MYC KD 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.

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

Not available.

A multiprotein supercomplex controlling oncogenic signalling in lymphoma.

B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1. Gene expression profiling identified two major subtypes of DLBCL, known as germinal centre B cell-like and activated B cell-like (ABC)2,3, that show poor outcomes after immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase signalling cascade of SYK, BTK and PKCß to promote the assembly of the CARD11-BCL10-MALT1 adaptor complex, which recruits and activates IκB kinase4-6. Genome sequencing revealed gain-of-function mutations that target the CD79A and CD79B BCR subunits and the Toll-like receptor signalling adaptor MYD885,7, with MYD88(L265P) being the most prevalent isoform. In a clinical trial, the BTK inhibitor ibrutinib produced responses in 37% of cases of ABC1. The most striking response rate (80%) was observed in tumours with both CD79B and MYD88(L265P) mutations, but how these mutations cooperate to promote dependence on BCR signalling remains unclear. Here we used genome-wide CRISPR-Cas9 screening and functional proteomics to determine the molecular basis of exceptional clinical responses to ibrutinib. We discovered a new mode of oncogenic BCR signalling in ibrutinib-responsive cell lines and biopsies, coordinated by a multiprotein supercomplex formed by MYD88, TLR9 and the BCR (hereafter termed the My-T-BCR supercomplex). The My-T-BCR supercomplex co-localizes with mTOR on endolysosomes, where it drives pro-survival NF-κB and mTOR signalling. Inhibitors of BCR and mTOR signalling cooperatively decreased the formation and function of the My-T-BCR supercomplex, providing mechanistic insight into their synergistic toxicity for My-T-BCR+ DLBCL cells. My-T-BCR supercomplexes characterized ibrutinib-responsive malignancies and distinguished ibrutinib responders from non-responders. Our data provide a framework for the rational design of oncogenic signalling inhibitors in molecularly defined subsets of DLBCL.

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.

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.

Variation in Anesthesiology Provider-Volume for Complex Gastrointestinal Cancer Surgery: A Population-Based Study.

OBJECTIVE: Examine between-hospital and between-anesthesiologist variation in anesthesiology provider-volume (PV) and delivery of high-volume anesthesiology care. BACKGROUND: Better outcomes for anesthesiologists with higher PV of complex gastrointestinal cancer surgery have been reported. The factors linking anesthesiology practice and organization to volume are unknown. METHODS: We identified patients undergoing elective esophagectomy, hepatectomy, and pancreatectomy using linked administrative health data sets (2007-2018). Anesthesiology PV was the annual number of procedures done by the primary anesthesiologist in the 2 years before the index surgery. High-volume anesthesiology was PV>6 procedures/year. Funnel plots to described variation in anesthesiology PV and delivery of high-volume care. Hierarchical regression models examined between-anesthesiologist and between-hospital variation in delivery of high-volume care use with variance partition coefficients (VPCs) and median odds ratios (MORs). RESULTS: Among 7893 patients cared for at 17 hospitals, funnel plots showed variation in anesthesiology PV (median ranging from 1.5, interquartile range: 1-2 to 11.5, interquartile range: 8-16) and delivery of HV care (ranging from 0% to 87%) across hospitals. After adjustment, 32% (VPC 0.32) and 16% (VPC: 0.16) of the variation were attributable to between-anesthesiologist and between-hospital differences, respectively. This translated to an anesthesiologist MOR of 4.81 (95% CI, 3.27-10.3) and hospital MOR of 3.04 (95% CI, 2.14-7.77). CONCLUSIONS: Substantial variation in anesthesiology PV and delivery of high-volume anesthesiology care existed across hospitals. The anesthesiologist and the hospital were key determinants of the variation in high-volume anesthesiology care delivery. This suggests that targeting anesthesiology structures of care could reduce variation and improve delivery of high-volume anesthesiology care.

Patient-Reported Symptom Burden After Cancer Surgery in Older Adults: A Population-Level Analysis.

BACKGROUND: Older adults have unique needs for supportive care after surgery. We examined symptom trajectories and factors associated with high symptom burden after cancer surgery in older adults. PATIENTS AND METHODS: We conducted a population-level study of patients ≥ 70 years old undergoing cancer surgery (2007-2018) using prospectively collected Edmonton Symptom Assessment System (ESAS) scores. The monthly prevalence of moderate to severe symptoms (ESAS ≥ 4) for anxiety, depression, drowsiness, lack of appetite, nausea, pain, shortness of breath, tiredness, and poor wellbeing was computed over 12 months after surgery. RESULTS: Among 48,748 patients, 234,420 ESAS scores were recorded over 12 months after surgery. Moderate to severe tiredness (57.8%), poor wellbeing (51.9%), and lack of appetite (39.3%) were most common. The proportion of patients with moderate to severe symptoms was stable over the 1 month prior to and 12 months after surgery (< 5% variation for each symptom). There was no clinically significant change (< 5%) in symptom trajectory with the initiation of adjuvant therapy. CONCLUSIONS: Patient-reported symptom burden was stable for up to 1 year after cancer surgery among older adults. Neither surgery nor adjuvant therapy coincided with a worsening in symptom burden. However, the persistence of symptoms at 1 year may suggest gaps in supportive care for older adults. This information on symptom trajectory and predictors of high symptom burden is important to set appropriate expectations and improve patient counseling, recovery care pathways, and proactive symptom management for older adults after cancer surgery.

Low T-cell proportion in the tumor microenvironment is associated with immune escape and poor survival in diffuse large B-cell lymphoma.

The tumor microenvironment (TME) is important in the pathogenesis and prognosis of lymphoma. Previous studies have demonstrated that features of the diffuse large B-cell lymphoma (DLBCL) TME can be associated with prognosis, but questions remain about the mechanisms underlying these TME features, and the interplay between tumor cells and the local TME. Therefore, we performed multispectral immunofluorescence (mIF) using two 6-color panels to interrogate the cellular proportions of T-cell subsets, macrophages, and natural killer cells in 57 cases of de novo DLBCL treated with R-CHOP chemotherapy. We found that very low CD3+ T-cell proportion and low CD4+PD1+ and CD8+PD1+ T cells have poor survival compared to those with a high T-cell proportion. Also, cases with concurrently low TIM3 and PD1 have a poor prognosis. This poor prognosis with low T-cell proportion was validated using immune deconvolution of gene expression profiling data from 351 cases of DLBCL and an additional cohort of 53 cases of DLBCL using routine immunohistochemistry. In addition, cases with loss of B2M, HLA I and/or HLA II protein expression on the tumor cells also had a low T-cell proportion, providing evidence that lack of these proteins allows for immune evasion. Overall, our results show that patients with DLBCL with a low T-cell proportion in the TME have a poor survival when treated with R-CHOP and exhibit mechanisms of immune escape.

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.

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.

Targeting MYC and BCL2 by a natural compound for "double-hit" lymphoma.

Concurrent translocations of MYC and BCL2 lead to abnormal expression of both oncoproteins, which contribute to the aggressive clinical characteristics of double-hit lymphoma (DHL). An effective therapy for DHL remains an unmet clinical need. In this study, we showed that both Ca2+ /calmodulin-dependent protein kinase II δ (CAMKIIδ) and γ (CAMKIIγ) were highly expressed in DHL. Both isoforms of CAMKII stabilize c-Myc protein by phosphorylating it at Ser62, increase BCL2 expression, and promote DHL tumor growth. Inhibition of CAMKIIδ and CAMKIIγ by either berbamine (BBM) or one of its derivatives (PA4) led to the down regulation of c-Myc and BCL2 proteins. BBM/PA4 also exhibited anti-tumor efficacy in DHL cell lines and NSG xenograft models. Altogether, CAMKIIδ and CAMKIIγ appear to be critical for DHL tumor development and are promising therapeutic targets for DHL.

Impact of care by gynecologic oncologists on primary ovarian cancer survival: A population-based study.

OBJECTIVES: Timely treatment of epithelial ovarian cancer (EOC) by gynecologic oncologists (GOs) with a combination of surgery and/or chemotherapy has been advocated. Nonetheless, some patients are not assessed by GOs prior to starting their treatment or have surgery by non-GOs. This study aims to determine trends over time in non-mucinous EOC care and to evaluate the impact of care on survival. METHODS: Using province-wide administrative data, patients diagnosed with non-mucinous EOC between 2007 and 2018 were identified. Multivariate Cox proportional hazards regression models were used to evaluate the impact of GO assessment prior to initiating treatment or having surgery done by a non-GO on mortality. RESULTS: A total of 10,086 EOC patients were included between 2007 and 2018. During the study period, there was an 8% increase in GO assessment (79% in 2007 to 87% in 2018-19, p ≤  0.001) and a 19% increase in surgeries performed by GOs (69% in 2007 to 88% in 2018-19, p ≤ 0.001). On multivariate analysis, there was an increased hazard of all-cause mortality for patients not assessed by GOs before first treatment (Hazard ratio (HR): 1.61; 95% CI 1.46-1.79). There was an increased hazard of all-cause mortality if ovarian cancer surgery was performed by non-GOs (HR 2.03; 95% CI 1.80-2.30). CONCLUSION: Assessment by GO before starting initial treatment is associated with improved survival in women with non-mucinous EOC as the type of surgeon performing primary ovarian cancer surgery. Assessment by GO for all patients with new or suspected ovarian cancer diagnosis before initiation of primary treatment should be advocated.

Association Between Frailty and Time Alive and At Home After Cancer Surgery Among Older Adults: A Population-Based Analysis.

BACKGROUND: Although frailty is known to impact short-term postoperative outcomes, its long-term impact is unknown. This study examined the association between frailty and remaining alive and at home after cancer surgery among older adults. METHODS: Adults aged ≥70 years undergoing cancer resection were included in this population-based retrospective cohort study using linked administrative datasets in Ontario, Canada. The probability of remaining alive and at home in the 5 years after cancer resection was evaluated using Kaplan-Meier methods. Extended Cox regression with time-varying effects examined the association between frailty and remaining alive and at home. RESULTS: Of 82,037 patients, 6,443 (7.9%) had preoperative frailty. With median follow-up of 47 months (interquartile range, 23-81 months), patients with frailty had a significantly lower probability of remaining alive and at home 5 years after cancer surgery compared with those without frailty (39.1% [95% CI, 37.8%-40.4%] vs 62.5% [95% CI, 62.1%-63.9%]). After adjusting for age, sex, rural living, material deprivation, immigration status, cancer type, surgical procedure intensity, year of surgery, and receipt of perioperative therapy, frailty remained associated with increased hazards of not remaining alive and at home. This increase was highest 31 to 90 days after surgery (hazard ratio [HR], 2.00 [95% CI, 1.78-2.24]) and remained significantly elevated beyond 1 year after surgery (HR, 1.56 [95% CI, 1.48-1.64]). This pattern was observed across cancer sites, including those requiring low-intensity surgery (breast and melanoma). CONCLUSIONS: Preoperative frailty was independently associated with a decreased probability of remaining alive and at home after cancer surgery among older adults. This relationship persisted over time for all cancer types beyond short-term mortality and the initial postoperative period. Frailty assessment may be useful for all candidates for cancer surgery, and these data can be used when counseling, selecting, and preparing patients for surgery.