Best Medical Therapy for Asymptomatic Carotid Stenosis: Imminent or Ineffective?

Carotid artery disease accounts for approximately 20% of all ischemic strokes, a major cause of morbidity, and the fifth leading cause of death in the United States. Landmark trials in the 1990s, such as Asymptomatic Carotid Atherosclerosis Study and Asymptomatic Carotid Surgery Trial, establish carotid endarterectomy (CEA) plus best medical therapy (BMT) as the standard of care for patients with asymptomatic carotid stenosis over 60%. However, advances in medical therapy and the emergence of carotid artery stenting (CAS) have prompted a reevaluation of treatment efficacy. Recent studies have questioned the superiority of CEA over BMT alone in reducing stroke risk, suggesting no significant difference in outcomes with contemporary medical management. In addition, analysis from the U. S. Department of Veterans Affairs indicated minimal net benefit of CEA over BMT when accounting for all-cause mortality. Comparative studies have found no significant difference in long-term stroke-free survival between CEA and CAS. However, procedural risks vary, with higher myocardial infarction rates associated with CEA and higher stroke rates with CAS. Identifying high-risk plaques and patient-specific risk factors remains crucial. Meta-analyses have highlighted features such as neovascularization and lipid rich cores as predictors of stenosis progression and ischemic events. Ongoing research, particularly the CREST-2 trial, aims to provide clear guidance on the optimal treatment of asymptomatic carotid stenosis. This trial emphasizes stringent adherence to modern BMT protocols and includes comprehensive lifestyle modification programs. The evolving landscape of medical and surgical interventions necessitates continuous evaluation to optimize treatment strategies for asymptomatic carotid stenosis, which is the impetus for this review. Future findings from ongoing trials are expected to refine current guidelines and improve patient outcomes.

Thrombotic complications after radiofrequency and cyanoacrylate endovenous ablation: Outcomes of a multicenter real-world experience.

OBJECTIVE: Chronic venous insufficiency (CVI) affects >40% of the U.S. population; thus, intervention for symptomatic venous disease comprises a large portion of many vascular practices. The treatment of superficial CVI has evolved from open surgical treatment to minimally invasive endovenous closure, including both thermal and nonthermal techniques. Thrombotic complications of thermal ablation have been well reported, with an overall complication rate of <2%. However, a paucity of high-powered, real-world data is available on the thrombotic outcomes of nonthermal techniques. In the present study, we compared the incidence of endovenous heat-induced thrombosis (EHIT) and endovenous glue-induced thrombosis (EGIT) in a large cohort of patients with CVI. METHODS: A retrospective review was conducted at two tertiary-level institutions of patients who had undergone superficial endovenous ablation from 2018 to 2021. The patient demographics, comorbidities, and periprocedural outcomes were collected through medical record review. A Caprini risk assessment model score was assigned using the information available from the electronic medical records. The patients were categorized by procedure type (ClosureFast [Medtronic Inc, Minneapolis, MN] radiofrequency ablation [RFA] vs VenaSeal [Medtronic Inc] cyanoacrylate glue closure [CAG]). The primary end point was the incidence of EHIT or EGIT. The secondary end point was the incidence of deep vein thrombosis and/or pulmonary embolism. RESULTS: A total of 803 patients had undergone 1096 procedures during the study period. Their mean age was 62 ± 15 years, and 67% were women. Of the 1096 procedures, 700 were RFA and 396 were CAG procedures, with a combined closure rate of 98% by postprocedure duplex ultrasound at 7 days. The average Caprini score was 5.2 ± 1.8 (RFA, 5.0; vs CAG, 5.4; P < .001). The incidence of EHIT and EGIT was 1.9% and 1.3%, respectively (P = .57). The deep vein thrombosis rate was 0.1% in the RFA cohort and 0.3% in the CAG cohort (P = .81). A comparative analysis of thermal vs nonthermal techniques was performed. A univariate analysis of the risk factors for EHIT and EGIT revealed no significant factors predisposing to thrombotic events. CONCLUSIONS: The results from the present study have demonstrated the safety of RFA and CAG closure techniques for CVI, with lower thrombotic rates than previously reported. Further work might help to identify how these results can be achieved across all venous ablative techniques for CVI, even for patient populations with advanced venous disease and possibly a greater than average risk of thrombotic events.

Thrombotic complications of superficial endovenous ablation: a contemporary review of thermal and non-thermal techniques.

Endovenous ablation has become the preferred means to treat superficial venous insufficiency. Ablative technologies have evolved to include a variety of both thermal and non-thermal techniques. The reported thrombotic complications of endovenous heat induced thrombosis (EHIT) and deep venous thrombosis (DVT) associated with thermal techniques are low (<2% overall). However, the limited data on newer non-thermal technologies suggest these modalities may have thrombotic complication rates upwards of 6%. Additionally, the pathophysiology of thrombotic events related to mechanochemical ablative techniques may differ from EHIT, and thus, may have different implications for management. Described is a case report of a stroke after cyanoacrylate ablation of the great saphenous vein, and a review of the current literature reporting the thrombotic complications associated with current thermal and non-thermal techniques. There exists a need for high-volume studies on newer ablative techniques to fully understand their associated thrombotic complications. This review highlights the need for a comprehensive classification system and standard treatment algorithm encompassing of thrombotic complications associated with both thermal and non-thermal ablative techniques.

Circulating Tumor DNA Analysis to Assess Risk of Progression after Long-term Response to PD-(L)1 Blockade in NSCLC.

PURPOSE: Treatment with PD-(L)1 blockade can produce remarkably durable responses in patients with non-small cell lung cancer (NSCLC). However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression. EXPERIMENTAL DESIGN: In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (progression-free survival ≥ 12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing. Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n = 18) or by targeted sequencing (n = 6). RESULTS: Thirty-one patients with NSCLC with long-term benefit to PD-(L)1 blockade were identified, and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; in contrast, all 4 patients with detectable ctDNA eventually progressed [Fisher P < 0.0001; positive predictive value = 1, 95% confidence interval (CI), 0.51-1; negative predictive value = 0.93 (95% CI, 0.80-0.99)]. CONCLUSIONS: ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 blockade and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.

Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical Outcomes.

INTRODUCTION: EGFR-mutant lung cancers are clinically and genomically heterogeneous with concurrent RB transcriptional corepressor 1 (RB1)/tumor protein p53 (TP53) alterations identifying a subset at increased risk for small cell transformation. The genomic alterations that induce lineage plasticity are unknown. METHODS: Patients with EGFR/RB1/TP53-mutant lung cancers, identified by next-generation sequencing from 2014 to 2018, were compared to patients with untreated, metastatic EGFR-mutant lung cancers without both RB1 and TP53 alterations. Time to EGFR-tyrosine kinase inhibitor discontinuation, overall survival, SCLC transformation rate, and genomic alterations were evaluated. RESULTS: Patients with EGFR/RB1/TP53-mutant lung cancers represented 5% (43 of 863) of EGFR-mutant lung cancers but were uniquely at risk for transformation (7 of 39, 18%), with no transformations in EGFR-mutant lung cancers without baseline TP53 and RB1 alterations. Irrespective of transformation, patients with EGFR/TP53/RB1-mutant lung cancers had a shorter time to discontinuation than EGFR/TP53- and EGFR-mutant -only cancers (9.5 versus 12.3 versus 36.6 months, respectively, p = 2 × 10-9). The triple-mutant population had a higher incidence of whole-genome doubling compared to NSCLC and SCLC at large (80% versus 34%, p < 5 × 10-9 versus 51%, p < 0.002, respectively) and further enrichment in triple-mutant cancers with eventual small cell histology (seven of seven pre-transformed plus four of four baseline SCLC versus 23 of 32 never transformed, respectively, p = 0.05). Activation-induced cytidine deaminase/apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like mutation signature was also enriched in triple-mutant lung cancers that transformed (false discovery rate = 0.03). CONCLUSIONS: EGFR/TP53/RB1-mutant lung cancers are at unique risk of histologic transformation, with 25% presenting with de novo SCLC or eventual small cell transformation. Triple-mutant lung cancers are enriched in whole-genome doubling and Activation-induced cytidine deaminase/apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like hypermutation which may represent early genomic determinants of lineage plasticity.

Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers.

PURPOSE: Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored. EXPERIMENTAL DESIGN: We identified all patients with metastatic EGFR exon19del or L858R-mutant lung cancers treated with first/second-generation EGFR tyrosine kinase inhibitors (TKIs) with pretreatment next-generation sequencing data (MSK-IMPACT assay). The effect of TMB on time-to-treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. EGFR wild-type lung adenocarcinoma samples were used for comparison. RESULTS: Among 153 patients with EGFR-mutant lung cancer, TMB was lower compared with EGFR wild-type (n = 1,849; median 3.77 vs. 6.12 mutations/Mb; P < 0.0001) with a broad range (0.82-17.9 mutations/Mb). Patients with EGFR-mutant lung cancer whose tumors had TMB in the high tertile had shorter TTD (HR, 0.46; P = 0.0008) and OS (HR, 0.40; P = 0.006) compared with patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD, P = 0.006; OS, P = 0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared with high TMB (HR = 0.57, P = 0.01; HR = 0.50, P = 0.02, respectively). In paired pretreatment and postprogression samples, TMB was increased at resistance (median 3.42 vs. 6.56 mutations/Mb; P = 0.008). CONCLUSIONS: TMB is negatively associated with clinical outcomes in metastatic patients with EGFR-mutant lung cancer treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy.See related commentary by Cheng and Oxnard, p. 899.

Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.

Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC.