Citations

Aim: According to the results of the MASTRO I living systematic review and meta-analysis, use of the EmboTrap Revascularization ® Device in the treatment of acute ischemic stroke (AIS) results in higher rates of good functional outcomes (90-day modified Rankin Scale [mRS] 0–2) compared with use of the Trevo ® Retriever or the Solitaire™ Revascularization Device. The aim of this analysis was to assess the potential economic impact of achieving improved functional outcomes for three commonly used stent retrievers (SRs) in the treatment of AIS. Methods: An economic model with short-term and long-term costs, representing a healthcare system perspective was developed using a decision tree to simulate a cohort of 1000 hypothetical patients treated for AIS with mechanical thrombectomy (MT) using EmboTrap, Trevo or Solitaire SRs. Based on the proportion of patients who achieved a 90-day mRS score of 0–2 or 3–5 for each device reported in MASTRO I (excluding patients not surviving after 90 days), this model estimated per-patient costs and the associated incremental cost savings. Results are reported from the healthcare system perspective in the US, Canada, the UK, Sweden, Germany, France, Italy, Spain, Belgium and The Netherlands. Results: Across all ten countries, the use of EmboTrap during MT was associated with the lowest short-term (ranging from €8412 in Italy to $66,525 in the US), long-term (ranging from €5249 in Italy to $25,757 in the US) and total (ranging from €13,661 in Italy to $92,282 in the US) per-patient costs. The total per-patient cost was higher with Trevo (ranging from €14,601 in Italy to $97,487 in the US) and Solitaire (ranging from €14,840 in Italy to $98,814 in the US). Cost savings were highest when comparing EmboTrap versus Solitaire, followed by EmboTrap versus Trevo, with Trevo versus Solitaire having the smallest cost savings. Results of sensitivity and scenario analyses supported the robustness of the base-case results. Conclusion: Across the ten countries, treating patients with AIS with EmboTrap resulted in lower short-term, long-term and total costs to the payer. With rising healthcare costs and limited hospital budgets, these results suggest EmboTrap proves to be an evidence-based economical choice of SR for hospitals and healthcare systems.

Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer. Newer advances in common and novel oncogenic drivers continue to occur at vigorous speed, making it challenging to stay up to date with the rapidly evolving field. In this article, we review the emerging perspectives in the treatment of actionable targets in lung cancer. We focus on the development of newer KRAS-directed therapies, particularly on non-G12C mutations, pan-RAS inhibitors, and RAS-GTP inhibitors. We also describe the current standard of care for EGFR- and ALK-altered NSCLC and dive into the novel treatments expected to be in the clinic soon. A similar approach is taken toward MET, HER2, RET, ROS1, and FGFR alterations as emerging targets in non-small-cell lung cancer. Finally, we conclude this review with the current body of evidence for targeting TROP-2 as a novel target, potentially of importance in post-targeted therapy scenarios.

Abstract Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is a rare and aggressive lymphoma with molecular heterogeneity not well characterize. In this study, we performed next-generation sequencing analysis for a large number of DNA and RNA samples from patients with PT-DLBCL. DNA sequencing analysis identified ≥ 3 chromosomes with copy number variations (CNVs) and microsatellite instability as prognostic biomarkers, rather than MYD88 mutations and genetic subtypes. Remarkably, targeted RNA-seq analysis in 195 patients revealed that TP53 mutations with a ≥ 40% variant allele frequency had significantly adverse prognostic impact, and that a 150-gene expression signature subdivided PT-DLBCL into two distinct clusters, termed as testicular lymphoma tumor (TLT) and microenvironment (ME) subtypes. The TLT subtype featured upregulation of genes involved in B-cell receptor signaling, cell cycle, DNA damage and repair, higher frequencies of CNVs and MYD88 mutations, elder ages, larger tumor sizes, and significantly poorer survival. Genomic microRNA profiling analysis identified significantly differentially expressed microRNAs between 113 PT-DLBCL and 180 systemic DLBCL patients, and further subdivided the PT-DLBCL cohort by microRNA signatures. The subcohort with upregulation of 16 microRNAs associated with PT-DLBCL and testicular tissue expression had significantly better survival. This study revealed characteristic genetic, gene expression, and microRNA profiles and heterogeneity in PT-DLBCL.

Abstract Myelodysplastic syndromes/neoplasms (MDSs) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the US Food and Drug Administration, (eg, luspatercept, ivosidenib, decitabine/cedazuridine, and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories, including criteria for risk stratification and eligibility, response definitions, time-to-event end points, transfusion end points, functional assessments, and biomarker development. Strategies to address these challenges and optimize future clinical trial design for patients with MDS are presented here.

ABSTRACT Objective To estimate the incidence, prevalence, patient characteristics and healthcare utilization patterns of moderate to severe thyroid eye disease (TED) in the United States. Design Retrospective review of medical and prescription claims data from the Inovalon deidentified claims database. Patients Patients with moderate to severe TED were identified based on specific and sensitive definitions using International Classification of Diseases (ICD) codes selected by a group of TED specialists. Results The incident moderate to severe TED population included 3364 and 1730 patients using the sensitive and specific definitions, respectively. After adjusting for age and gender, corresponding incidence rates in the sensitive and specific populations were 8.97 (13.49 in women and 4.27 in men) and 4.37 (6.59 in women and 2.05 in men) per 100,000 person‐years, respectively. The prevalent population included 16,310 and 8018 patients using the sensitive and specific definitions, respectively, corresponding to adjusted prevalence rates of 44.13 (66.00 in women and 21.39 in men) and 20.55 (31.18 in women and 9.50 in men) per 100,000 persons. A preponderance of women was observed, and comorbidity rates were high, with > 40% of prevalent patients experiencing hypertension. Steroids were the most frequently prescribed medication. The impact of teprotumumab was not captured, since this study only included claims data through 2019. Conclusions The estimated incidence and prevalence rates of TED demonstrate the considerable impact of this disease in the United States, making the creation of a specific ICD code imperative for effective healthcare planning and management.

Introduction: Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS), traditionally referred to as primary CNS lymphoma (PCNSL), is a rare type of primary large B-cell lymphoma of immune-privileged sites with significantly poorer prognosis than systemic DLBCL. Genetic profiles of PCNSL were widely studied, whereas the tumor microenvironment has not been well characterized. Patients and Methods: A series of molecular analyses were performed using DLBCL FFPE tissues collected by the International Lymphoma Consortium. First, multiplex fluorescent immunohistochemistry (mfIHC) using antibodies for CD20, PAX5, CD3, CD4, CD8, FOXP3, CD45RO, CD68, CD56, PD-1, PD-L1, PD-L2, and CTLA-4 was performed on PCNSL tissues from 121 immunocompetent patients and de novo systemic DLBCL tissues from 405 patients. Digital quantification results for 405 patients with EBV-negative systemic DLBCL or primary testicular (PT) DLBCL have been reported previously. The preliminary mfIHC results of PCNSL will be presented. Second, mfIHC for multiple B cell biomarkers, CD3, CD4, CD8, CD68, CD163, CD11c, and CD31 were performed for 10 PCNSL validation cases, 24 PT-DLBCL and 451 systemic DLBCL tissues (unpublished). Third, RNA samples were extracted and sequenced for the targeted 1408 cancer-associated genes, successfully in 142 PCNSL cases, including 102 cases evaluated by either of these two mfIHC panels and additional 40 PCNSL cases, Results: First, in the first large mfIHC cohort, PCNSLs compared with de novo systemic nodal or extranodal DLBCL had significantly higher mean/median CD56+ cell densities whereas lower T cell densities (consistent with the immune privilege), as well as lower CD45RO+, PD-1+, and FOXP3+ percentages in T cells whereas higher CD4¯CD8¯ double-negative percentages in T cells. Prognostic analysis in the PCNSL cohort showed that high CD56+ cell densities and high CD45RO+CD8+ T cell densities were associated with significantly poorer and better patient survival, respectively, which are opposite to their prognostic effects in systemic DLBCL as previously reported. Twelve patients had very high PD-L1 expression in B cells and significantly poorer survival in the PCNSL cohort. Second, as validation, the 10 PCNSL cases in the second mfIHC study showed significantly less T cells than systemic DLBCL and PT-DLBCL cases, and low CD8 T cell densities and having low percentage of CD8 T cells adjacent to tumor cells were associated with significantly poorer survival. Immunofluorescence landscapeand spatial analysisrevealed significant differences in immune privilege between PCNSL and PT-DLBCL. Third, gene expression profiling analysis by targeted RNA-seq identified 282 significantly differentially expressed genes between PCNSL and systemic DLBCL, referred to as the PCNSL signature. Unsupervised clustering analysis divided the PCNSL cohort into two clusters, which had no significant difference in MYD88 mutation frequencies analyzed at the mRNA level. Importantly, the cluster with higher expression of many neural glial genes in the PCNSL signature had significantly poorer survival, which remained significant in multivariate analysis adjusting for clinical factors and/or treatments, two PCNSL subcohorts (as training and validation cohorts), and methotrexate-treated patients. NCAM1 (Neural Cell Adhesion Molecule 1, encoding CD56) was among the upregulated PCNSL signature genes, explaining the poorer prognosis associated with higher CD56+ cell densities in PCNSL by the mfIHC analysis. Summary: Our studies represent the largest immunophenotypic and gene expression profiling studies currently in PCNSL, a rare type of primary DLBCL of immune-privileged sites. Multiplex immunofluorescence revealed the immune landscape in PCNSL in comparison with systemic and testicular DLBCL, and identified prognostic immune biomarkers. Targeted RNA-seq identified a PCNSL gene signature enriched with neuronal-glial genes and showing significant prognostic effect in PCNSL. These novel findings in the PCNSL microenvironment warrant further studies.

Background: Financial toxicity (FT), or the negative impact of medical expenses experienced by patients, is a known adverse effect of cancer treatment that result in worse health outcomes for patients. However, there is limited literature investigating FT in lymphoma with even less data on predictors such as age, gender, and socioeconomic factors. As lymphoma treatment options expand, it is vital to understand the impact of these treatments on patients' financial well-being. We investigate FT through patient reported outcomes from the Lymphoma Epidemiology of Outcomes (LEO), a large multi-institution prospective cohort study of non-Hodgkin lymphoma (NHL). Methods: Patients with newly diagnosed NHL were enrolled into the LEO cohort from 2015-2020. Clinical, pathology and treatment data were abstracted from medical records, and participants were offered self-administered surveys at enrollment and selected follow-up time points. Participants were included if they completed at least four of six survey questions on FT adapted from the Medical Expenditure Panel Survey (MEPS) within the first year after diagnosis. Questions focused on either material hardship (unable to cover costs; file for bankruptcy; borrow money; work extra job or hours) or psychological stress (worried about paying large medical bills). We evaluated FT as answering positively to any question (any vs none). Associations with FT were evaluated using chi-squared tests. All analyses were performed using R (v4.2.2). Results: 3202 patients completed at least four survey questions relating to FT. Mean age at diagnosis was 62 years (18-94), 56% were male, and majority identified as white (90%). Characteristics associated with FT are reported (p<0.001). FT was more likely in younger patients: 18-25 years (64%, 30/47), 26-44 years (73%, 299/313), and 45-64 years (58%, 799/1375) as compared to those 65-79 years (36%, 459/1272) and ≥80 years (35%, 69/195). FT was highest in patients without a high school diploma (54%, 45/84), followed by patients with a high school diploma (52%, 209/402), and an associate's degree (57%, 358/627). It was lowest in patients with a bachelor's (45%, 224/296) or post-graduate degree (39.6%, 216/545). Higher FT was seen in those receiving disability income (65%, 47/72); whereas less FT was seen in retired patients (36%, 299/828). FT rates inversely correlated with income: 65% for income < $21,000 (184/283), 61% for $21,000- $39,999 (224/370) and 60% for $40,000-$65,999 (293/491). Lower FT noted for income range of $66,000-$106,000 (47%, 323/681) or > $106,000 (37%, 324/872). Patients separated from a partner (82.9%, 19/23) had the highest FT, followed by patients living with a partner (64%, 48/75), divorced (56%, 103/184), and never married (53.4%, 79/148). Patients who were married (47%, 793/1672) or widowed (41%, 60/146) reported the lowest FT. Higher FT was reported in DLBCL (55%, 631/1146), MCL (55%, 172/315), and TCL (53%, 119/226) when compared to FL (44%, 327/746), MZL (44%, 137/316), and other NHL (44%, 200/453). This is likely related to treatment as more FT was seen in patients who received an anthracycline and/or alkylator containing therapy (54%, 1066/1963) versus non-systemic (43%, 120/278) and observation (35%, 168/483). In multivariable analyses, FT strongly correlated with age at diagnosis, household income, and treatment type. The odds ratio and 95% confidence intervals for the most significant category within each variable are as follows: age per 1 year (0.96, [0.95-0.97]), income > $106,000 vs < $21,000 (0.28, [0.21-0.38]), and observation vs anthracycline and/or alkylator (0.56, [0.44-0.71]). Conclusion: Nearly 50% of patients with lymphoma experience FT, seen as material hardship and psychological stress, within the first year of diagnosis. Patients with a younger age (18-44), less education, and lower household income reported higher levels of FT; whereas those who were retired or married/widowed reported lower FT. Lymphoma subtypes that require more anthracycline and/or alkylator containing therapy imposed higher FT. Understanding these risk factors can help clinicians identify patients who may benefit from additional resources during lymphoma management.

Importance Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined. Objective To develop consensus best practices for delivering NT to patients with localized PDAC. Design, Setting, and Participants This study used a modified Delphi approach consisting of 2 rounds of voting, and a series of virtual conferences (from October to December 2023) to reach expert consensus on candidate best practice statements generated from a systematic review of the literature and expert opinion. An interdisciplinary panel was formed including 47 North American experts from surgical, medical, and radiation oncology, radiology, pathology, gastroenterology, integrative oncology, anesthesia, pharmacy, nursing, cancer care delivery research, and nutrition as well as patient and caregiver stakeholders. Main Outcome and Measures Statements that reached 75% agreement or greater were included in final consensus statements. Results Of the 47 participating panel members, 27 (57.64%) were male, and the mean (SD) age was 47.6 (8.2) years. Physicians reported completing training a mean (SD) 14.6 (8.6) years prior and seeing a mean (SD) 110.6 (38.4) patients with PDAC annually; 35 (77.7%) were in academic practice. Final consensus was reached on 82 best practices for delivering NT. Of these, 38 statements focused on pre-NT practices, including diagnosis and staging (n = 15), evaluation and optimization (n = 20), and decision-making (n = 3); 29 statements defined best practices during NT, including initiation (n = 3), delivery of therapy (n = 8), restaging practices (n = 12), and management of complications during NT (n = 6); and 15 best practices were identified to guide treatment post-NT, focusing on surgery (n = 7), pathology (n = 4), and follow-up (n = 3). Conclusions Using a modified Delphi consensus technique, best practice guidelines were developed focusing on the optimal standards for delivering NT to patients with localized PDAC. Given the prognostic importance of completing multimodality therapy, efforts to standardize and optimize the delivery of NT represent an immediate opportunity to decrease care variation and improve outcomes for patients with PDAC. Future research should focus on validating and implementing best practice standards into clinical practice.

Abstract GBM AGILE(NCT03970447) is a phase 2/3 Bayesian adaptive registration platform trial testing multiple therapies against a common control. Paxalisib, a PI3K/mTOR inhibitor, is the 3rd arm in the trial to conclude evaluation. METHODS Paxalisib was open to patients with newly diagnosed unmethylated (NDU) and recurrent (RD) glioblastoma, with three possible signatures: NDU, RD, and All(NDU+RD). Arm enrollment occurred Dec2020 through May2022. Control patients were enrolled from study initiation (July2019) and were treated with temozolomide(NDU) or lomustine(RD). GBM AGILE investigational arms have 1 or 2 stages, with adaptive randomization in stage 1 and fixed randomization if arms continue to stage 2. Efficacy is based on OS hazard ratio(HR) of Arm/Control. Efficacy goal is final Bayesian probability ≥ 98% for HR<1.00 in combined Stages. An Arm continues to Stage 2 if Bayesian predictive power (PP) ≥ 0.8. An Arm stops accruing in Stage 1 if it reaches maximal sample size(N) or does not meet a minimum efficacy threshold (PP<0.25 for all signatures when N>50). Clinical cut-off is 12 months after accrual stops. The maximum N for paxalisib was approximately 150(Stage 1) and 50(Stage 2). RESULTS After paxalisib reached >150 patients in Stage 1, accrual stopped [Paxalisib/control N 54/75(NDU), 100/188(RD)]. Neither PP thresholds for moving to Stage 2 nor stopping for minimum efficacy were met. Following an unplanned public disclosure that the arm did not continue to stage 2, clinical cut-off for final analysis (planned May2023) was updated to public disclosure date (August2022). At final analysis mean HRs were 0.89(NDU), 1.25(RD), 1.05(All), probabilities of HR<1.00 of 0.72(NDU), 0.076(RD), 0.398(All). Model estimated median OS paxalisib/control (months) were 14.77/13.84(NDU) and 8.58/10.06(RD). CONCLUSION Paxalisib did not show survival benefit over cumulative control in final primary analysis; additional secondary analyses are being considered. GBM AGILE continues to rapidly and efficiently assess therapies in ND and RD glioblastoma.

Abstract One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.