Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial.

Mismatch repair deficiency (dMMR) is found in approximately 15% of non-metastatic colon cancers (CCs) and is characterized by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumors. Although patients with dMMR CC have limited benefit from chemotherapy, these tumors have been shown to respond exceptionally well to neoadjuvant anti-PD-1 plus anti-CTLA-4, with high rates of pathologic responses. Here, based on data from melanoma studies, we postulated a high efficacy and favorable toxicity profile of anti-PD-1 plus anti-LAG-3. In the NICHE-3 study, a total of 59 patients with locally advanced dMMR CC were treated with two 4-weekly cycles of nivolumab (480 mg) plus relatlimab (480 mg) before surgery. Pathologic response was observed in 57 of 59 (97%; 95% confidence interval (CI): 88-100%) patients, meeting the primary endpoint. Responses included 54 (92%; 95% CI: 81-97%) major pathologic responses (≤10% residual viable tumor) and 40 (68%; 95% CI: 54-79%) pathologic complete responses. With a median follow-up of 8 months (range, 2-19), one patient had recurrence of disease. The treatment displayed an acceptable safety profile, with all-grade and grade 3-4 immune-related adverse events (irAEs) occurring in 80% and 10% of patients, respectively. The most common irAEs were infusion-related reactions (29%), thyroid dysfunction (22%) and fatigue (20%). In conclusion, our results show that neoadjuvant nivolumab/relatlimab induces high rates of pathologic responses and that further investigation of this treatment in larger studies is warranted. These data add to the body of evidence in support of neoadjuvant immunotherapy regimens in dMMR CC. ClinicalTrials.gov identifier: NCT03026140 .

Correction: Groen et al. Use of Image-Guided Surgical Navigation during Resection of Locally Recurrent Rectal Cancer. Life 2022, 12, 645.

The authors wish to make the following corrections to this paper [...].

Use of Image-Guided Surgical Navigation during Resection of Locally Recurrent Rectal Cancer.

Surgery for locally recurrent rectal cancer (LRRC) presents several challenges, which is why the percentage of inadequate resections of these tumors is high. In this exploratory study, we evaluate the use of image-guided surgical navigation during resection of LRRC. Patients who were scheduled to undergo surgical resection of LRRC who were deemed by the multidisciplinary team to be at a high risk of inadequate tumor resection were selected to undergo surgical navigation. The risk of inadequate surgery was further determined by the proximity of the tumor to critical anatomical structures. Workflow characteristics of the surgical navigation procedure were evaluated, while the surgical outcome was determined by the status of the resection margin. In total, 20 patients were analyzed. For all procedures, surgical navigation was completed successfully and demonstrated to be accurate, while no complications related to the surgical navigation were discerned. Radical resection was achieved in 14 cases (70%). In five cases (25%), a tumor-positive resection margin (R1) was anticipated during surgery, as extensive radical resection was determined to be compromised. These patients all received intraoperative brachytherapy. In one case (5%), an unexpected R1 resection was performed. Surgical navigation during resection of LRRC is thus safe and feasible and enables accurate surgical guidance.

Ten-year risk of stroke in patients with previous cerebral infarction and the impact of carotid surgery in the Asymptomatic Carotid Surgery Trial.

BACKGROUND: Silent brain infarcts are common in patients at increased risk of stroke and are associated with a poor prognosis. In patients with asymptomatic carotid stenosis, similar adverse associations were claimed, but the impact of previous infarction or symptoms on the beneficial effects of carotid endarterectomy is not clear. Our aim was to evaluate the impact of prior cerebral infarction in patients enrolled in the Asymptomatic Carotid Surgery Trial, a large trial with 10-year follow-up in which participants whose carotid stenosis had not caused symptoms for at least six months were randomly allocated either immediate or deferred carotid endarterectomy. METHODS: The first Asymptomatic Carotid Surgery Trial included 3120 patients. Of these, 2333 patients with baseline brain imaging were identified and divided into two groups irrespective of treatment assignment, 1331 with evidence of previous cerebral infarction, defined as a history of ischemic stroke or transient ischemic attack > 6 months prior to randomization or radiological evidence of an asymptomatic infarct (group 1) and 1002 with normal imaging and no prior stroke or transient ischemic attack (group 2). Stroke and vascular deaths were compared during follow-up, and the impact of carotid endarterectomy was observed in both groups. RESULTS: Baseline characteristics of patients with and without baseline brain imaging were broadly similar. Of those included in the present report, male gender and hypertension were more common in group 1, while mean ipsilateral stenosis was slightly greater in group 2. At 10 years follow-up, stroke was more common among participants with cerebral infarction before randomization (absolute risk increase 5.8% (1.8-9.8), p = 0.004), and the risk of stroke and vascular death was also higher in this group (absolute risk increase 6.9% (1.9-12.0), p = 0.007). On multivariate analysis, prior cerebral infarction was associated with a greater risk of stroke (hazard ratio = 1.51, 95% confidence interval: 1.17-1.95, p = 0.002) and of stroke or other vascular death (hazard ratio = 1.30, 95% confidence interval: 1.11-1.52, p = 0.001). At 10 years, greater absolute benefits from immediate carotid endarterectomy were seen in those patients with prior cerebral infarction (6.7% strokes immediate carotid endarterectomy vs. 14.7% delayed carotid endarterectomy; hazard ratio 0.47 (0.34-0.65), p = 0.003), compared to those lower risk patients without prior cerebral infarction (6.0% vs. 9.9%, respectively; hazard ratio 0.61 (0.39-0.94), p = 0.005), though it must be emphasized that the first Asymptomatic Carotid Surgery Trial was not designed to test this retrospective and non-randomized comparison. CONCLUSIONS: Asymptomatic carotid stenosis patients with prior cerebral infarction have a higher stroke risk during long-term follow-up than those without prior cerebral infarction. Evidence of prior ischemic events might help identify patients in whom carotid intervention is particularly beneficial.

7.0 T MRI detection of cerebral microinfarcts in patients with a symptomatic high-grade carotid artery stenosis.

In the current study, the presence of cerebral cortical microinfarcts (CMIs) was evaluated in a series of 21 patients with a symptomatic high-grade >50% stenosis of the carotid artery. A T2-weighted fluid-attenuated inversion recovery sequence and a T1-weighted turbo field echo sequence of the brain were obtained at 7.0 Tesla magnetic resonance imaging. Primary study endpoint was the number of CMIs and macroinfarcts. In total, 53 cerebral infarcts (35 macroinfarcts; 18 CMIs) were found ipsilateral to the symptomatic carotid artery, in 14 patients (67%). In four of these patients, both CMIs and macroinfarcts were visible. In the contralateral hemisphere, seven infarcts (five macroinfarcts and two CMIs) were found in five patients (24%). In the ipsilateral hemispheres, the number of CMIs and macroinfarcts were significantly correlated (P=0.02). Unpaired comparison of medians showed that the number of CMIs in the ipsilateral hemisphere was significantly higher than the number of CMIs in the contralateral hemisphere (P=0.04). No significant correlation was found between stenosis grade and the number of any infarct. The current study shows that in symptomatic patients with significant extracranial carotid artery stenosis, CMIs are part of the total cerebrovascular burden and these CMIs prevail with a similar pattern as observed macroinfarcts.

Seven-tesla magnetic resonance imaging of atherosclerotic plaque in the significantly stenosed carotid artery: a feasibility study.

OBJECTIVES: The objective of this study was to assess the feasibility of carotid vessel wall imaging at 7.0 for T magnetic resonance imaging (MRI) in a series of patients with a symptomatic greater than 70% stenosis of the internal carotid artery. MATERIALS AND METHODS: First, a series of 6 healthy volunteers were scanned at 3.0 T and 7.0 T MRI to perform a signal-to-noise ratio comparison between these 2 field strengths. Second, in patients with a greater than 70% stenosed carotid artery, a 7.0 T MRI protocol, consisting of a dual-echo turbo spin echo sequence (echo times of 45 and 150 milliseconds) and a T1-weighted turbo spin echo sequence, was obtained. Lumen and vessel wall were delineated for interobserver and intraobserver reproducibility, and signal intensity distribution in the most severely stenosed part of the internal carotid artery was correlated with different plaque components on histopathologic findings. RESULTS: The mean (SD) signal-to-noise ratio in the vessel wall was 42 (12) at 7.0 T and 24 (4) at 3.0 T. Nineteen patients were included, but technical issues yielded carotid MRI data of 14 patients available for the final analysis. Of these patients, 4 were diagnosed with stroke, 7 were diagnosed with a transient ischemic attack, and 3 were diagnosed with amaurosis fugax. Intraclass correlation coefficient of the agreements of lumen and vessel wall determination between 2 observers and between the repeated measures of 1 observer were above 0.80 in both 3.0 T and 7.0 T data sets of the healthy volunteers and also in the 7.0 T data set of the patients. Signal hyperintensity in the 7.0 T magnetic resonance images was inversely proportional to calcification. Other correlations between plaque components and signal intensity could not be confirmed. CONCLUSIONS: This first series of patients with carotid atherosclerotic plaque who were scanned at 7.0 T MRI shows that 7.0 T MRI enables to adequately determine lumen and vessel wall areas. Signal hyperintensity in these 7.0 T magnetic resonance images was inversely proportional to calcification. However, at this stage, no other correlations between histologic findings and vessel wall contrast were found. Implementation of in vivo high-resolution 7.0 T MRI of plaque components for risk stratification remains challenging. Future development of hardware and software is still needed to attain a more robust setup and to enable complete plaque characterization, similar to what is currently possible with multiple MRI sequences at 1.5 T and 3.0 T MRI.

Risk of stroke from new carotid artery occlusion in the Asymptomatic Carotid Surgery Trial-1.

BACKGROUND AND PURPOSE: In the Asymptomatic Carotid Surgery Trial-1 (ACST-1), 3120 patients with tight asymptomatic carotid stenosis were randomly assigned to medical treatment alone or to carotid endarterectomy and appropriate medication. Successful carotid endarterectomy significantly reduced 10-year stroke risk in younger patients. This study was undertaken to determine the risk of new occlusion and stroke during trial follow-up. METHODS: Patients with contralateral occlusion at trial entry (n=276) or incomplete duplex follow-up (n=137) were excluded. Risk of occlusion and stroke in patients with occlusion was estimated by Kaplan-Meier analysis. Cox proportional hazard regression models were used to determine risk factors for developing new occlusion and stroke. RESULTS: Median follow-up in 2707 patients was 80.0 months (interquartile range, 52.0-115.0). New occlusions occurred in 197 patients (1.1% per annum) but were more likely to occur in arteries with tight stenosis and in unoperated patients. Overall risk of stroke was 7.6% (95% confidence interval [CI], 6.6-8.7) and 15.5% (95% CI, 13.6-17.4) at 5 and 10 years, respectively; for patients with new occlusion, this significantly increased to 17.0% (95% CI, 11.6-22.4) and 20.8% (95% CI, 14.1-26.2), respectively (P<0.001). Stroke was significantly more likely to occur in patients developing occlusion (hazard ratio, 1.78; 95% CI, 1.26-2.51) irrespective of allocated treatment. CONCLUSIONS: New occlusions were uncommon after carotid endarterectomy in ACST-1. During long-term follow-up, occlusion and stroke were commoner among patients with ≥ 70% stenosis, most of whom had not undergone carotid endarterectomy. Occlusion was an independent prognostic risk factor for occurrence of stroke.

Selective external endarterectomy in patients with ipsilateral symptomatic internal carotid artery occlusion.

BACKGROUND: Selective endarterectomy of external carotid artery (ECA) stenosis has been considered a therapeutic option for patients presenting with symptomatic ipsilateral internal carotid artery (ICA) occlusion to correct cerebral hypoperfusion or eliminate a source of emboli. However, data are scarce, and the long-term benefit of ECA revascularization remains unclear. Our objective was to study the operative results and durability of selective ECA endarterectomy in patients presenting with cerebrovascular symptoms in association with nonacute ipsilateral ICA occlusion. METHODS: This was a retrospective analysis of 27 consecutive patients who underwent selective ECA endarterectomy in a single center between 2000 and 2010. All patients presented with neurologic symptoms (<6 months of surgery, 78% repeat events) referable to an ipsilateral occlusion of the ICA and concomitant stenosis of the ECA. We assessed the perioperative clinical outcome <30 days and at midterm follow-up (mean, 31.6 months). Patency was defined as freedom of duplex ultrasound detected ≥ 50% restenosis. RESULTS: Endarterectomy of the ECA was successful in 26 patients (96.3%) with one ECA found occluded at surgery. No perioperative deaths occurred. In the 30 days after surgery, one patient developed an ipsilateral disabling ischemic stroke (3.7%), and one patient (3.7%) had a myocardial infarction. At follow-up, nine patients had died: one of a fatal ischemic stroke, six of non-vascular-related causes, and two of unknown causes. At 3 years, 83% (standard error, 8%) of patients were free from stroke or death, and 80% (standard error, 8%) of the operated-on arteries were patent. Five patients developed restenosis ≥ 50% (n = 2, asymptomatic) or occlusion (n = 3, one symptomatic) ≤ 3 months, and two other patients developed late asymptomatic restenosis. CONCLUSIONS: Selective endarterectomy of the ECA in symptomatic patients with an ipsilateral occlusion of the ICA is a feasible procedure with an acceptable perioperative risk. Most patients remain stroke-free during follow-up and have a low rate of symptomatic restenosis.

Asymptomatic carotid artery stenosis and the risk of ischemic stroke according to subtype in patients with clinical manifest arterial disease.

BACKGROUND AND PURPOSE: Because best medical treatment is improving, the risk of stroke in asymptomatic carotid artery stenosis (ACAS) may decline. We evaluated the risk of ischemic stroke and stratified it according to stroke subtype in patients with ACAS during long-term follow-up. METHODS: In total, 4319 consecutive patients in the Second Manifestations of Arterial disease study with clinically manifest arterial disease or specific risk factors, but without a history of cerebrovascular disease, were included. Degree of stenosis was evaluated with duplex ultrasound scanning. Strokes during follow-up were classified according to subtype. Cox-proportional hazard-regression models were used to evaluate the relationship between ACAS and future stroke. RESULTS: We identified 293 (6.8%) patients with ACAS 50% to 99%, of whom 193 had 70% to 99% stenosis. In these subgroups, mean follow-up was 6.2 and 6.0 years, respectively. In total, 94 ischemic strokes occurred, of which 8 in ACAS 50% to 99% patients. The any territory annual ischemic stroke risk was 0.4% in 50% to 99% ACAS and 0.5% per year for 70% to 99% ACAS patients. The risk of ischemic stroke was not significantly increased in patients with ACAS 70% to 99% (hazard ratio, 1.5; 95% confidence interval, 0.7-3.5). Patients with ACAS 50% to 99% and ACAS 70% to 99% tended to have nonsignificantly more large vessel disease strokes (hazard ratio, 1.5; 95% confidence interval, 0.5-4.2 and hazard ratio, 1.7; 95% confidence interval, 0.5-5.6). CONCLUSIONS: Patients with clinically manifest arterial disease or type 2 diabetes mellitus have a low risk of developing ischemic stroke, irrespective of its subtype and independent of the degree of ACAS stenosis.

Stenting versus surgery in patients with carotid stenosis after previous cervical radiation therapy: systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Patients with both carotid stenosis and previously cervical radiation therapy are considered "high risk" for carotid endarterectomy (CEA). Carotid angioplasty and stenting (CAS) seems a reasonable alternative, but neither the operative risk for CEA nor the effectiveness of CAS has been proven. The purpose of this study was to evaluate perioperative and long-term outcome of both procedures in patients with radiation therapy. METHODS: A systematic search strategy with the synonyms "carotid artery stenosis" and "cervical irradiation" was conducted in MEDLINE and EMBASE databases. To provide and compare estimates of outcomes, pooled and metaregression analyses were performed. RESULTS: Twenty-seven articles comprising 533 patients undergoing radiation therapy (361 CAS and 172 CEA) fulfilled our inclusion criteria. Pooled analysis showed perioperative risk for "any cerebrovascular adverse event" (CVE) of 3.9% (95% CI, 2.3%-6.7%) in CAS studies against 3.5% (95% CI, 1.5%-8.0%) in CEA studies (P=0.77). Risk for cranial nerve injury (CNI) after CEA was 9.2% (95% CI, 3.7%-21.1%) versus none after CAS. Late outcome showed rates of CVE favoring CEA (P=0.014). The rate of restenosis >50% was significantly higher in patients treated with CAS compared with CEA (P<0.003). CONCLUSIONS: Both CAS and CEA proved to be feasible revascularization techniques with low risk for CVE. Although patients undergoing CEA had more temporary CNI, higher rates of late CVE and restenosis were identified after CAS.

Hyperintense carotid plaque on T(1)-weighted turbo-field echo MRI in symptomatic patients with low-grade carotid stenosis and carotid occlusion.

BACKGROUND: In addition to stenosis grading, magnetic resonance imaging (MRI) may provide valuable information about plaque 'status', e.g. hyperintense vulnerable carotid plaque, associated with higher morbidity and mortality. In the present study, we investigated the prevalence, clinical and radiological correlates of hyperintense carotid plaques on T(1)-weighted turbo-field echo (T(1)w-TFE) MRI in patients with ischemic symptoms. METHODS: A total of 153 patients presenting with transient ischemic attack or ischemic infarct, studied with contrast-enhanced magnetic resonance angiography (CEMRA), were retrospectively examined. Stenosis grade was obtained from CEMRA images, presence or absence of hyperintense carotid plaque from T(1)w-TFE MRI. Stenosis grade and baseline characteristics were compared between patients with and without a hyperintense plaque. RESULTS: Twenty-eight patients (18%) showed one or more hyperintense internal carotid (ICA) plaques. Hyperintense plaques were found in patients with <50% stenosis (6 of 158 ICAs), 50-70% stenosis (4 of 11), >70% stenosis (14 of 74) and carotid occlusion (4 of 28). Presence of hyperintense plaque was associated with older age (70 vs. 62 years; p < 0.05), higher prevalence of cardiac disease (61 vs. 28%; p < 0.01), ischemic infarct as presenting symptom (37 vs. 14%; p < 0.01), ischemic cerebral lesions on MRI (63 vs. 32%; p < 0.01), and the ICA on the patients' symptomatic side (70 vs. 42%; p < 0.01). CONCLUSIONS: More than one third of patients with 50-70% stenosis present with a hyperintense plaque. This subgroup of patients could in the future possibly benefit from more aggressive medicinal therapy or revascularization.

Mechanisms of gender-related outcome differences after carotid endarterectomy.

OBJECTIVE: Large randomized trials have confirmed a difference in outcome after carotid endarterectomy (CEA) between men and women. In this review, we aimed to provide an overview of the gender-specific characteristics causing these perioperative and long-term outcome differences between men and women after CEA. METHODS: A systematic search strategy with the synonyms of 'gender' and 'carotid endarterectomy' was conducted from PubMed and EMBASE databases. Only 11 relevant studies specifically discussing gender-specific related characteristics and their influence on outcome after CEA could be identified. RESULTS: Due to the limited number of included studies, pooling of findings was impossible, and results are presented in a descriptive manner. Each included study described only one possible gender-specific factor. Differences in carotid artery diameter, sex hormones, sensitivity for antiplatelet therapy, plaque morphology, occurrence of microembolic signals, and restenosis rate have all been suggested as gender-specific characteristics influencing outcome after CEA. CONCLUSION: Higher embolic potential in women and relatively stable female plaque morphology are the best-described factors influencing the difference in outcomes between men and women. However, the overall evidence for outcome differences by gender-specific characteristics in the literature is limited.