The effect of a single dose of nivolumab prior to isolated limb perfusion for patients with in-transit melanoma metastases: An interim analysis of a phase Ib/II randomized double-blind placebo-controlled trial (NivoILP trial).

OBJECTIVE: ILP has shown to achieve high response rates in patients with melanoma ITM. Possibly there is a synergistic mechanism of action of ILP and anti-PD1. The aim of this trial was to investigate the safety and efficacy of adding a single dose of systemic anti-PD1 to isolated limb perfusion (ILP) for patients with melanoma in-transit metastases (ITM). METHODS: In this placebo controlled double-blind phase Ib/II trial, patients with melanoma ITM were randomized 1:1 to either a single systemic dose of nivolumab or placebo one day prior to ILP. The primary endpoint was complete response (CR) rate at three months, and safety in terms of incidence and severity of adverse events (AEs). RESULTS: A total of 20 patients were included. AEs of any grade occurred in 90% of patients in the nivolumab arm and in 80% in the placebo arm within three months after ILP. Grade 3 AEs were reported in 40% and 30% respectively, most commonly related to wound infection, wound dehiscence, or skin necrosis. There were no grade 4 or 5 AEs reported. The CR rate was 75% in the nivolumab arm and 60% in the placebo arm. The 1-year local progression-free rate was 86% in the nivolumab arm and 67% in the placebo arm. The 1-year OS was 100% in both arms. CONCLUSION: For patients with melanoma ITM, the addition of a single systemic dose of nivolumab the day before ILP is considered safe and feasible with promising efficacy. Accrual will continue in a phase 2 trial.

Isolated hyperthermic perfusions for cutaneous melanoma in-transit metastasis of the limb and uveal melanoma metastasis to the liver.

Patients with cutaneous melanoma can develop in-transit metastases (ITM), most often localized to limbs. For patients with uveal melanoma that develop metastatic disease, the overall majority develop isolated liver metastases. For these types of metastases, regional cancer therapies have evolved as effective treatments. Isolated limb perfusion (ILP), isolated limb infusion (ILI), isolated hepatic perfusion (IHP) and percutaneous hepatic perfusion (PHP) achieve a high local concentration of chemotherapy with minimal systemic exposure. This review discusses the mechanism and available literature on locoregional treatment modalities in the era of modern immunotherapy.

Efficacy of indocyanine green fluorescence for the identification of non-palpable breast tumours: systematic review.

BACKGROUND: Accurate tumour localization is crucial for precise surgical targeting and complete tumour removal. Indocyanine green fluorescence, an increasingly used technique in oncological surgery, has shown promise in localizing non-palpable breast tumours. The aim of this systematic review was to describe the efficacy of indocyanine green fluorescence for the identification of non-palpable breast tumours. METHODS: A systematic literature search was performed in PubMed, Embase, and the Cochrane Library, including studies from 2012 to 2023. Studies reporting the proportion of breast tumours identified using indocyanine green fluorescence were included. The quality of the studies and their risk of bias were appraised using the Methodological Index for Non-Randomized Studies ('MINORS') tool. The following outcomes were collected: identification rate, clear resection margins, specimen volume, operative time, re-operation rate, adverse events, and complications. RESULTS: In total, 2061 articles were screened for eligibility, resulting in 11 studies, with 366 patients included: two RCTs, three non-randomized comparative studies, four single-arm studies, and two case reports. All studies achieved a 100 per cent tumour identification rate with indocyanine green fluorescence, except for one study, with an identification rate of 87 per cent (13/15). Clear resection margins were found in 88-100 per cent of all patients. Reoperation rates ranged from 0.0 to 5.4 per cent and no complications or adverse events related to indocyanine green occurred. CONCLUSION: Indocyanine green fluorescence has substantial theoretical advantages compared with current routine localization methods. Although a limited number of studies were available, the current literature suggests that indocyanine green fluorescence is a useful, accurate, and safe technique for the intraoperative localization of non-palpable breast tumours, with equivalent efficacy compared with other localization techniques, potentially reducing tumour-positive margins.

Oncolytic intralesional therapy for metastatic melanoma.

In-transit metastasis (ITM) develop in approximately 1 in 10 patients with melanoma and the disease course can vary widely. Surgical resection is the gold-standard treatment; however, ITM are often surgically unresectable due to size, distribution, and/or anatomic involvement. Oncolytic viral therapies are one category of non-surgical treatment options available for ITM. They induce tumor cell lysis and systemic anti-tumor activity through selective infection of tumor cells by naturally occurring or genetically modified factors. While there are numerous oncolytic viral therapies in various stages of development for the treatment of ITM, this discussion focuses on the mechanism and available literature for the two most established herpes virus-based therapies.

Sentinel Lymph Node Mapping in Breast Cancer Patients Through Fluorescent Imaging Using Indocyanine Green: The INFLUENCE Trial.

OBJECTIVE: The aim was to compare the (sentinel) lymph node detection rate of indocyanine green (ICG)-fluorescent imaging versus standard-of-care 99m Tc-nanocoilloid for sentinel lymph node (SLN)-mapping. BACKGROUND: The current gold standard for axillary staging in patients with breast cancer is sentinel lymph node biopsy (SLNB) using radio-guided surgery using radioisotope technetium ( 99m Tc), sometimes combined with blue dye. A promising alternative is fluorescent imaging using ICG. METHODS: In this noninferiority trial, we enrolled 102 consecutive patients with invasive early-stage, clinically node-negative breast cancer. Patients were planned for breast conserving surgery and SLNB between August 2020 and June 2021. The day or morning before surgery, patients were injected with 99m Tc-nanocolloid. In each patient, SLNB was first performed using ICG-fluorescent imaging, after which excised lymph nodes were tested with the gamma-probe for 99m Tc-uptake ex vivo, and the axilla was checked for residual 99m Tc-activity. The detection rate was defined as the proportion of patients in whom at least 1 (S)LN was detected with either tracer. RESULTS: In total, 103 SLNBs were analyzed. The detection rate of ICG-fluorescence was 96.1% [95% confidence interval (95% CI)=90.4%-98.9%] versus 86.4% (95% CI=78.3%-92.4%) for 99m Tc-nanocoilloid. The detection rate for pathological lymph nodes was 86.7% (95% CI=59.5%-98.3%) for both ICG and 99m Tc-nanocoilloid. A median of 2 lymph nodes were removed. ICG-fluorescent imaging did not increase detection time. No adverse events were observed. CONCLUSIONS: ICG-fluorescence showed a higher (S)LN detection rate than 99m Tc-nanocoilloid, and equal detection rate for pathological (S)LNs. ICG-fluorescence may be used as a safe and effective alternative to 99m Tc-nanocoilloid for SLNB in patients with early-stage breast cancer.

A Clinical Validation Study of Anatomical Risk Scoring for Procedural Stroke in Patients Treated by Carotid Artery Stenting in the International Carotid Stenting Study.

OBJECTIVES: Vascular anatomy of the aortic arch and supra-aortic arteries has been suggested as influencing the risk of carotid artery stenting (CAS). The expert opinion based Delphi anatomical risk (DAR) score was developed to predict difficulty of CAS in relation to procedural stroke risk, and thereby aid patient selection. The aim was to validate the DAR score in the context of a randomised clinical trial. METHODS: In this post hoc analysis of the International Carotid Stenting Study (ICSS), only patients treated by CAS with available pre-procedural CT angiography (CTA) were included. Patients with tortuous anatomy unsuitable for stenting were excluded from ICSS. CTA based vascular anatomy was rated by two independent observers. Every possible combination of anatomy resulted in a risk score, divided in four categories of expected risk (low, < 5.0; low-intermediate, 5.0-5.9; high-intermediate, 6.0-6.9; high, ≥ 7.0). Binomial logistic regression was used to assess the relationship between anatomical risk score and procedural risk of any stroke. Differences between predefined age groups were also assessed. RESULTS: A total of 275 patients were included. Interobserver reliability for all anatomical risk factors was high (κ = 0.76-0.84). In total, 16 strokes (6%) occurred in the procedural period. No significant relationship was observed between the DAR score and risk of procedural stroke, with the risk of stroke being 9% in the high risk vs. 4% in the low risk categories (p = .49). A higher mean DAR score was observed in patients ≥70 years compared with younger patients (4.6 ± 1.5 vs. 3.9 ± 1.4, p < .001), which was mainly explained by higher rates of arch atheroma (44% vs. 20%, p < .001). Prolonged intervention duration was significantly associated with increased stroke risk (11% vs. 4%, p < .04), but not with the DAR score. CONCLUSIONS: No statistically significant association was found between anatomical difficulty, as defined in the DAR score, and procedural stroke risk. However, the small sample size potentially rendered the study underpowered to detect group differences, and confirmation with a larger sample is essential.

Editor's Choice - Cerebral Hyperperfusion Syndrome After Carotid Artery Stenting: A Systematic Review and Meta-analysis.

INTRODUCTION: Cerebral hyperperfusion syndrome (CHS) is a preventable cause of stroke after carotid endarterectomy (CEA). There are currently no pooled data available on the incidence of CHS after carotid artery stenting (CAS). The aim of this review was to assess the relevance of CHS in the procedural stroke rate following CAS. METHOD: A systematic search on incidence rates of CHS after CAS was conducted in the MEDLINE, EMBASE, and Cochrane databases in November 2017. A meta-regression analysis was performed on CHS to explain heterogeneity and determine the impact of potential risk factors on observed CHS. The methodological quality of the included studies was assessed using the Cowley criteria. RESULTS: The pooled CHS risk across 33 studies concerning 8731 CAS patients was 4.6% (3.1-6.8%). Stroke occurred in 47% of CHS patients, of which 54% were fatal or disabling. Average time from procedure to symptoms was 12 h (IQR 8-36 h). Impaired cerebrovascular reserve (CVR) was associated with a higher risk of CHS after CAS (RR 5.18; 95% CI 1.0-26.8; p = .049). Symptomatic status was associated with a lower risk of CHS (RR 0.20; 95% CI 0.07-0.59; p = .001). CONCLUSION: CHS is a serious and frequent complication in patients undergoing carotid angioplasty with stenting, and is most likely to occur in the very early post-procedural period. Future studies are encouraged to investigate the effect of intensive haemodynamic monitoring, including blood pressure control and assessment of cerebral blood flow, on the incidence of stroke caused by CHS after CAS.

Clinical Experience amongst Surgeons in the Asymptomatic Carotid Surgery Trial-1.

INTRODUCTION: Hospital volume may influence the outcomes of carotid revascularization, but in trials the effect of the clinical experience of individual surgeons on procedural outcome is less certain. We assessed perioperative event rates amongst centers with different trial entry volumes and also the effects of individual operator experience in the first Asymptomatic Carotid Surgery Trial-1 (ACST-1). METHODS: In 126 centers participating in ACST-1, surgeons were classified according to their in-trial experience (group A: 50 cases; group B: 51-100 cases; group C: >100 cases), center enrolment volume (group I: <30 patients; group II: 30-75 patients; group III: >75 patients) and center annual hospital volume (group 1: <40 carotid endarterectomies (CEAs); group 2: 40-75 CEAs; group 3: >75 cases). Differences in perioperative event rates were compared using logistic regression analysis. RESULTS: In centers with the most clinical experience compared with those with least experience (groups C vs. A), the number of strokes or deaths was 8 of 275 (2.9%) versus 24 of 810 (3.0%) with OR 0.99 (95% CI 0.44-2.25, p = 0.986). Numbers of strokes or death in high enrolment centers compared with those in low enrolment centers (groups III vs. I) was 20 of 680 (2.9%) versus 21 of 580 (3.6%) with OR 0.81 (95% CI 0.43-1.51, p = 0.921). In centers with a high annual volume compared with those of low annual volume (groups 3 vs. 1), numbers of strokes and death were non-significantly lower, 26 of 823 (3.2%) versus 19 of 422 (4.5%) with OR 0.68 (95% CI 0.37-1.26, p = 0.386). Cumulative stroke risk at 5 and 10 years were similar among different levels of reported clinical experience, enrolment volume and annual hospital volume. CONCLUSION: Although our data did not demonstrate an association between perioperative complications and operators' experience, enrolment volume or annual hospital volume, rates of stroke or death were numerically lower in both high enrolment and high annual volume centers. This lack of association could be explained by an overall low procedural risk in ACST-1.

The Mid-Term Clinical Follow-Up Using Drug-Eluting Balloons on Tibial Artery "De Novo" Lesions in Patients With Critical Limb Ischemia: A Cohort Study.

RATIONALE: Restenosis due to intimal hyperplasia (IH) is a major clinical issue that affects the success of lower limb endovascular surgery. After 1 year, restenosis occurs in 40% to 60% of the treated vessels. The possibility to reduce IH using local antiproliferative drugs, such as taxols, has been the rationale for the clinical applications of drug-eluting stents and drug-eluting balloons (DEBs). The purpose of this study was to evaluate the clinical and instrumental efficacy of DEBs versus simple percutaneous transluminal angioplasty (PTA) in patients affected by chronic limb ischemia (CLI) with tibial artery "de novo" lesions. METHODS: A retrospective analysis was performed and included all consecutive patients who underwent endovascular treatment for CLI in our centers between January 2011 and March 2013. Inclusion criteria were (1) "de novo" tibial artery stenosis and (2) Rutherford class >4. Lesions were further divided by TransAtlantic Inter-Societal Consensus (TASC) classification into groups A, B, C, and D. RESULTS: Between January 2010 and March 2013, a total of 138 patients underwent simple PTA or DEB for CLI, and the groups were clinically and demographically homogenous. We decided to use DEBs in 70 cases. An improvement in the Rutherford Scale in cumulative and single TASC lesions classification was better in the DEB group (74% vs 51%; P = .024) at 24 months than in the PTA group. In the DEB group, the increase in ankle-brachial index was significantly higher than in the PTA group (P = .039). CONCLUSIONS: Our experience in addition to the existing literature supports the use of DEB in patients with CLI Rutherford class >3.

The Mechanism of Procedural Stroke Following Carotid Endarterectomy within the Asymptomatic Carotid Surgery Trial 1.

INTRODUCTION: Understanding the pathophysiological mechanism of procedural stroke during carotid intervention may help reduce the risk of stroke in those undergoing surgery. We therefore studied the features of procedural strokes within the first Asymptomatic Carotid Surgery Trial-1 (ACST-1) to identify the underlying pathophysiological mechanism. METHODS: In ACST-1, 3,120 patients with severe asymptomatic carotid stenosis thought suitable for surgery were randomized to CEA or indefinite deferral of surgery. Information on procedural (within 30 days) stroke type, laterality, severity and timing was collected. Eight possible mechanisms were defined: embolism from the carotid artery, haemodynamic, thrombosis or occlusion of the carotid artery, hyperperfusion syndrome, cardioembolic, either carotid embolic or haemodynamic, either carotid embolic or thrombotic occlusion, or undetermined. RESULTS: Procedural strokes occurred in 53 patients (2.7%). Strokes were predominantly ischaemic (n = 43; 81%), ipsilateral to the treated artery (n = 42; 79%), often occurred on the day of the operation (n = 32; 60%) and in over half the patients, were disabling or fatal (n = 27; 51%). The identified stroke mechanism was carotid embolic (n = 7), haemodynamic (n = 5), thrombosis or occlusion of the carotid artery (n = 9), hyperperfusion (n = 7), cardioembolic (n = 3), 'probably carotid embolic or haemodynamic' (n = 7), 'probably carotid embolic or thrombotic occlusion' (n = 3) and undetermined in 12 cases. CONCLUSION: In ACST-1, the risk of procedural stroke was low. Most strokes (60%) occurred on the day of the procedure and were caused by thrombosis or thrombotic occlusion of the ipsilateral carotid artery. These findings emphasize the importance of immediate assessment of the treated carotid artery when a stroke occurs after CEA.

Screw needle cytology of thyroid nodules is associated with a lower non-diagnostic rate compared to fine needle aspiration.

BACKGROUND: Fine needle aspiration (FNA) cytology is the method of choice to exclude malignancy in thyroid nodules. A major limitation of thyroid FNA is the relatively high rate (13-17%) of non-diagnostic samples. The aim of this study is to determine the diagnostic yield of a screw needle compared to the conventional FNA. METHODS: We retrospectively analysed thyroid nodule cytology of all patients that underwent thyroid nodule fine needle or screw needle aspiration between July 2007 and July 2012 in a single academic medical centre. Cytology results were categorized according to the Bethesda classification system. RESULTS: In total, 644 punctures of thyroid nodules from 459 patients were available for analysis. The screw needle was used 531 times, and the conventional fine needle 113 times. The percentage of non-diagnostic cytology was significantly lower in the screw needle samples than in the fine needle samples (3% vs 17%, P<0.001). CONCLUSION: This study shows a significantly better diagnostic performance of the screw needle compared to the conventional fine needle in cytology of thyroid nodules.

PKCepsilon regulates behavioral sensitivity, binding and tolerance to the CB1 receptor agonist WIN55,212-2.

The cannabinoid CB1 receptor (CB1) is one of the most abundant G protein-coupled receptors in the brain, but little is known about the mechanisms that modulate CB1 receptor signaling. Here, we show that inhibition or null mutation of the epsilon isozyme of protein kinase C (PKCepsilon) selectively enhances behavioral responses to the CB1 agonist WIN55,212-2 in mice, but not to the structurally unrelated CB1 agonist CP55,940. Binding affinity for [(3)H] WIN55,212-2 was increased in brain membranes from PKCepsilon(-/-) mice compared with PKCepsilon(+/+) mice. There was no difference in binding of the inverse agonist [(3)H] SR141716A. In addition, repeated administration of WIN55,212-2 produced greater analgesic and thermal tolerance in PKCvarepsilon(-/-) mice compared with PKCepsilon(+/+)mice. These results indicate that PKCvarepsilon selectively regulates behavioral sensitivity, CB1 receptor binding and tolerance to WIN55,212-2.