Local Tumour Control Following Microwave Ablation: Protocol for the Prospective Observational CIEMAR Study.

PURPOSE: Microwave ablation (MWA) is a treatment modality for colorectal liver metastases (CRLM). While potentially curative, more information is needed on factors that contribute to long-term local tumour control. The prospective multicentre observational study CIRSE Emprint Microwave Ablation Registry aims to prospectively collect real-world technical data and clinical outcomes on patients treated with MWA in CRLM. METHODS: Eligible patients are adults with up to 9 local treatment naïve CRLM of ≤ 3 cm completely treatable with either MWA alone or MWA with resection and/or radiotherapy within 8 weeks. Data are collected, at baseline, every 3 months until 12 months, and thereafter every 6 months until the end of the study. The primary outcome measure is local tumour control. Secondary outcome measures are overall survival, (hepatic-) disease-free survival, time-to-progression untreatable by ablation, systemic therapy vacation, safety, and quality of life. Covariates related to the primary outcome measure will be assessed using a stratified log-rank test and an univariable Cox proportional hazard regression. A sample size of 500 patients with 750 lesions produces a two-sided 95% confidence interval with a precision equal to 0.057. RESULTS: Between September 2019 and December 2022, 500 patients have been enrolled with at least 976 treated tumours. CONCLUSION: The prospective observational CIEMAR study will provide valuable insights into the real-world use of MWA, helping in the future patient selection and clarifying factors that may contribute to long-term local tumour control. TRIAL REGISTRATION: NCT03775980.

Research in interventional oncology: How sound is the evidence base?

INTRODUCTION: Interventional oncology (IO) is an essential component of cancer care, which has gained substantial recognition in recent years. The aim of this review is to evaluate the level of evidence supporting IO and its inclusion in cancer treatment guidelines. METHODS: A literature search of the PubMed database was performed to identify publication numbers and types for IO treatments published between 2012 and 2022. Selected cancer treatment guidelines and recommendations were reviewed for their inclusion of IO treatments. RESULTS: With 68%, the majority of studies on IO treatments are case reports while randomised controlled trials (RCTs) amount only to 7% of studies. Despite this, IO studies have generated sufficient data to support the inclusion of IO treatments in cancer treatment guidelines and recommendations. This was frequently based on large prospective patient cohorts that corresponded to 24% (20% non-randomised studies and 4% observational studies) of all analysed studies rather than RCTs. CONCLUSION: The level of evidence underpinning IO, as well as inclusion of IO in treatment guidelines and recommendations have increased substantially in recent years, indicating the growing importance and acceptance of IO in cancer care. The difficulty in conducting RCTs in IO is mitigated by the observation that they are not necessary to achieve guideline-inclusion. Nevertheless, it is crucial to conduct well-designed research projects to further consolidate the position of IO in the field of oncology. This will ensure that IO continues to evolve and meet the needs of cancer patients worldwide.

Predictive Factors for Adverse Event Outcomes After Transarterial Radioembolization with Yttrium-90 Resin Microspheres in Europe: Results from the Prospective Observational CIRT Study.

BACKGROUND: Using data collected in the prospective observational study CIRSE Registry for SIR-Spheres Therapy, the present study aimed at identifying predictors of adverse events (AEs) following transarterial radioembolization (TARE) with Yttrium-90 resin microspheres for liver tumours. METHODS: We analysed 1027 patients enrolled between January 2015 and December 2017 and followed up for 24 months. Four hundred and twenty-two patients with hepatocellular carcinoma (HCC), 120 with intrahepatic carcinoma (ICC), 237 with colorectal liver metastases and 248 with liver metastases from other primaries were included. Prognostic factors were calculated with a univariable analysis by using the overall AEs burden score (AEBS). RESULTS: All-cause AEs were reported in 401/1027 (39.1%) patients, with AEs associated with TARE, such as abdominal pain (16.6%), fatigue (17%), and nausea (11.7%) reported most frequently. Grade 3 or higher AEs were reported in 92/1027 (9%) patients. Reports on grade ≥ 3 gastrointestinal ulcerations (0.4%), gastritis (0.3%), radiation cholecystitis (0.2%) or radioembolization-induced liver disease (0.5%) were uncommon. Univariable analysis showed that in HCC, AEBS increased for Eastern Cooperative Oncology Group (ECOG) 0 (p = 0.0045), 1 tumour nodule (0.0081), > 1 TARE treatment (p = 0.0224), no prophylactic embolization (p = 0.0211), partition model dosimetry (p = 0.0007) and unilobar treatment target (0.0032). For ICC, > 1 TARE treatment was associated with an increase in AEBS (p = 0.0224), and for colorectal liver metastases, ECOG 0 (p = 0.0188), > 2 prior systemic treatments (p = 0.0127), and 1 tumour nodule (p = 0.0155) were associated with an increased AEBS. CONCLUSION: Our study confirms that TARE is a safe treatment with low toxicity and a minimal impact on quality of life.

Factors impacting survival after transarterial radioembolization in patients with hepatocellular carcinoma: Results from the prospective CIRT study.

Background & Aims: Transarterial radioembolization (TARE) with Yttrium-90 resin microspheres is an established treatment option for patients with hepatocellular carcinoma (HCC). However, optimising treatment application and patient selection remains challenging. We report here on the effectiveness, safety and prognostic factors, including dosing methods, associated with TARE for HCC in the prospective observational CIRT study. Methods: We analysed 422 patients with HCC enrolled between Jan 2015 and Dec 2017, with follow-up visits every 3 months for up to 24 months after first TARE. Patient characteristics and treatment-related data were collected at baseline; adverse events and time-to-event data (overall survival [OS], progression-free survival [PFS] and hepatic PFS) were collected at every 3-month follow-up visit. We used the multivariable Cox proportional hazard model and propensity score matching to identify independent prognostic factors for effectiveness outcomes. Results: The median OS was 16.5 months, the median PFS was 6.1 months, and the median hepatic PFS was 6.7 months. Partition model dosimetry resulted in improved OS compared to body surface area calculations on multivariable analysis (hazard ratio 0.65; 95% CI 0.46-0.92; p = 0.0144), which was confirmed in the exact matching propensity score analysis (hazard ratio 0.56; 95% CI 0.35-0.89; p = 0.0136). Other independent prognostic factors for OS were ECOG-performance status >0 (p = 0.0018), presence of ascites (p = 0.0152), right-sided tumours (p = 0.0002), the presence of portal vein thrombosis (p = 0.0378) and main portal vein thrombosis (p = 0.0028), ALBI grade 2 (p = 0.0043) and 3 (p = 0.0014). Adverse events were recorded in 36.7% of patients, with 9.7% of patients experiencing grade 3 or higher adverse events. Conclusions: This large prospective observational dataset shows that TARE is an effective and safe treatment in patients with HCC. Using partition model dosimetry was associated with a significant improvement in survival outcomes. Impact and implications: Transarterial radioembolization (TARE) is a form of localised radiation therapy and is a potential treatment option for primary liver cancer. We observed how TARE was used in real-life clinical practice in various European countries and if any factors predict how well the treatment performs. We found that when a more complex but personalised method to calculate the applied radiation activity was used, the patient responded better than when a more generic method was used. Furthermore, we identified that general patient health, ascites and liver function can predict outcomes after TARE. Clinical trial number: NCT02305459.

Prognostic Factors for Effectiveness Outcomes After Transarterial Radioembolization in Metastatic Colorectal Cancer: Results From the Multicentre Observational Study CIRT.

BACKGROUND: Transarterial radioembolisation (TARE) with Yttrium-90 resin microspheres is a treatment option for patients with metastatic colorectal cancer in the liver (mCRC). A better understanding of the prognostic factors and treatment application can improve survival outcomes. METHODS: We analysed the safety and effectiveness of 237 mCRC patients included in the prospective observational study CIRSE Registry for SIR-Spheres Therapy (CIRT) for independent prognostic factors for overall survival (OS), progression-free survival (PFS) and hepatic progression-free survival (hPFS) using the Cox proportional-hazard model. RESULTS: The median OS was 9.8 months, median PFS was 3.4 months and median hPFS was 4.2 months. Independent prognostic factors for an improved overall survival were the absence of extra-hepatic disease (P= .0391), prior locoregional procedures (P= .0037), an Aspartate transaminase to Platelet Ratio Index (APRI) value of ≤0.40 (P< .0001) and International Normalized Ratio (INR) ≤1 (P= .0078). Partition model dosimetry resulted in improved OS outcomes compared to the body surface area model (P = .0120). Independent predictors for PFS were APRI >0.40 (P = .0416) and prior ablation (P = .0323), and for hPFS these were 2 to 5 tumor nodules (P = .0148), Albumin-bilirubin (ALBI) grade 3 (P = .0075) and APRI >0.40 (P = .0207). During the study, 95 of 237 (40.1%) patients experienced 197 adverse events, with 28 of 237 (11.8%) patients having a grade 3 or higher adverse events. CONCLUSION: Including easy-to-acquire laboratory markers INR, APRI, ALBI and using partition model dosimetry can identify mCRC patients that may benefit from TARE.

Safety, Feasibility and Technical Considerations from a Prospective, Observational Study-CIREL: Irinotecan-TACE for CRLM in 152 Patients.

CIREL, a prospective, Europe-wide, observational study aimed to assess the real-world feasibility and tolerability of irinotecan-based transarterial chemoembolization (LP-irinotecan TACE) for unresectable colorectal cancer liver metastases with regard to the treatment plan and adverse events (AEs). CIREL enrolled 152 eligible patients (≥18 years) with liver-only or dominant metastases treated with LP-irinotecan TACE following a multidisciplinary tumor board decision. Data were prospectively collected for baseline, the number of planned and performed sessions, and technical information and safety according to CTCAE 4.03/5.0. Results from 351 analyzed treatment sessions showed technical success for 99% of sessions, and 121 patients (79%) completed all planned sessions. Further, 60% of sessions were performed using opioids, 4% intra-arterial anesthetics, and 25% both. Additionally, 60% of patients experienced at least one peri-interventional AE of any grade; 8% of grade 3−4. Occurrence of AEs was related to larger liver-involvement (p < 0.001), bi-lobar disease (p = 0.002), and larger beads (p < 0.001). Using corticosteroids together with antiemetics showed reduced and lower grade vomiting (p = 0.01). LP-irinotecan TACE was tolerated well and had a high proportion of completed treatment plans. This minimally invasive locoregional treatment can be used together with concomitant systemic therapy or ablation.

The CIREL Cohort: A Prospective Controlled Registry Studying the Real-Life Use of Irinotecan-Loaded Chemoembolisation in Colorectal Cancer Liver Metastases: Interim Analysis.

PURPOSE: Transarterial chemoembolisation (TACE) using irinotecan-eluting beads is an additional treatment option for colorectal cancer liver metastases (CRLM) patients that are not eligible for curative treatment approaches. This interim analysis focuses on feasibility of the planned statistical analysis regarding data distribution and completeness, treatment intention, safety and health-related quality of life (HRQOL) of the first 50 patients prospectively enrolled in the CIrse REgistry for LifePearl™ microspheres (CIREL), an observational multicentre study conducted across Europe. METHODS: In total, 50 patients ≥ 18 years diagnosed with CRLM and decided to be treated with irinotecan-eluting LifePearl™ microspheres TACE (LP-irinotecan TACE) by a multidisciplinary tumour board. There were no further inclusion or exclusion criteria. The primary endpoint is the categorisation of treatment intention, and secondary endpoints presented in this interim analysis are safety, treatment considerations and HRQOL. RESULTS: LP-irinotecan TACE was conducted in 42% of patients as salvage therapy, 20% as an intensification treatment, 16% as a first-line treatment, 14% a consolidation treatment and 8% combination treatment with ablation with curative intent. Grade 3 and 4 adverse events were reported by 4% of patients during procedure and by 10% within 30 days. While 38% reported a worse, 62% reported a stable or better global health score, and 54% of patients with worse global health score were treated as salvage therapy patients. CONCLUSION: This interim analysis confirms in a prospective analysis the feasibility of the study, with an acceptable toxicity profile. More patients reported a stable or improved HRQOL than deterioration. Deterioration of HRQOL was seen especially in salvage therapy patients. TRIAL REGISTRATION: NCT03086096.

A multicentre, international, observational study on transarterial chemoembolisation in colorectal cancer liver metastases: Design and rationale of CIREL.

BACKGROUND: About 70-80% of patients with colorectal liver metastases appear as ineligible for a curative treatment approach. Transarterial chemoembolisation (TACE) using irinotecan-eluting beads has emerged as a promising treatment option in cases with irresectable liver metastases. Despite being in clinical practice for years, little is known about the treatment characteristics and outcomes when used as per routine hospital practice. METHODS: Patients with hepatic metastases from colorectal cancer origin, admitted to contributing centres to receive TACE with drug-eluting LifePearl® Microspheres loaded with irinotecan, as part of their standard care, will be consecutively added to the registry. Data will be collected until the end of study, loss to follow-up or death. Primary endpoint is the characterisation of the treatment usage at the selected sites in Europe. Secondary endpoints include outcome parameters, safety and toxicity, as well as quality of life. CONCLUSION AND AIMS: This multicentre, international, prospective observational study conducted in European centres plans to collect real-life data. This data will form an evidence-base from which conclusions can be drawn on how to improve patient selection and optimise treatment protocols when treating with TACE using irinotecan-eluting microspheres. Trial registration NCT03086096.

Induction of aquaporin 4-reactive antibodies in Lewis rats immunized with aquaporin 4 mimotopes.

Most cases of neuromyelitis optica spectrum disorders (NMOSD) harbor pathogenic autoantibodies against the water channel aquaporin 4 (AQP4). Binding of these antibodies to AQP4 on astrocytes initiates damage to these cells, which culminates in the formation of large tissue destructive lesions in the central nervous system (CNS). Consequently, untreated patients may become permanently blind or paralyzed. Studies on the induction and breakage of tolerance to AQP4 could be of great benefit for NMOSD patients. So far, however, all attempts to create suitable animal models by active sensitization have failed. We addressed this challenge and identified peptides, which mimic the conformational AQP4 epitopes recognized by pathogenic antibodies of NMOSD patients. Here we show that these mimotopes can induce the production of AQP4-reactive antibodies in Lewis rats. Hence, our results provide a conceptual framework for the formation of such antibodies in NMOSD patients, and aid to improve immunization strategies for the creation of animal models suitable for tolerance studies in this devastating disease.

Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination.

BACKGROUND: Antibodies to the myelin oligodendrocyte glycoprotein (MOG) are associated with a subset of inflammatory demyelinating diseases of the central nervous system such as acute disseminated encephalomyelitis and neuromyelitis optica spectrum disorders. However, whether human MOG antibodies are pathogenic or an epiphenomenon is still not completely clear. Although MOG is highly conserved within mammals, previous findings showed that not all human MOG antibodies bind to rodent MOG. We therefore hypothesized that human MOG antibody-mediated pathology in animal models may only be evident using species-specific MOG antibodies. METHODS: We screened 80 human MOG antibody-positive samples for their reactivity to mouse and rat MOG using either a live cell-based assay or immunohistochemistry on murine, rat, and human brain tissue. Selected samples reactive to either human MOG or rodent MOG were subsequently tested for their ability to induce complement-mediated damage in murine organotypic brain slices or enhance demyelination in an experimental autoimmune encephalitis (EAE) model in Lewis rats. The MOG monoclonal antibody 8-18-C5 was used as a positive control. RESULTS: Overall, we found that only a subset of human MOG antibodies are reactive to mouse (48/80, 60%) or rat (14/80, 18%) MOG. Purified serum antibodies from 10 human MOG antibody-positive patients (8/10 reactive to mouse MOG, 6/10 reactive to rat MOG), 3 human MOG-negative patients, and 3 healthy controls were tested on murine organotypic brain slices. Purified IgG from one patient with high titers of anti-human, mouse, and rat MOG antibodies and robust binding to myelin tissue produced significant, complement-mediated myelin loss in organotypic brain slices, but not in the EAE model. Monoclonal 8-18-C5 MOG antibody caused complement-mediated demyelination in both the organotypic brain slice model and in EAE. CONCLUSION: This study shows that a subset of human MOG antibodies can induce complement-dependent pathogenic effects in a murine ex vivo animal model. Moreover, a high titer of species-specific MOG antibodies may be critical for demyelinating effects in mouse and rat animal models. Therefore, both the reactivity and titer of human MOG antibodies must be considered for future pathogenicity studies.

Müller cells and retinal axons can be primary targets in experimental neuromyelitis optica spectrum disorder.

Recent work from our laboratory, using different models of experimental neuromyelitis optica spectrum disorder (NMOSD), has led to a number of observations that might be highly relevant for NMOSD patients. For example: (i) in the presence of neuromyelitis optica immunoglobulin G, astrocyte-destructive lesions can be initiated by CD4+ T cells when these cells recognize aquaporin 4 (AQP4), but also when they recognize other antigens of the central nervous system. The only important prerequisite is that the T cells have to be activated within the central nervous system by "their" specific antigen. Recently activated CD4+ T cells with yet unknown antigen specificity are also found in human NMOSD lesions. (ii) The normal immune repertoire might contain AQP4-specific T cells, which are highly encephalitogenic on activation. (iii) The retina might be a primary target of AQP4-specific T cells and neuromyelitis optica immunoglobulin G: AQP4-specific T cells alone are sufficient to cause retinitis with low-grade axonal pathology in the retinal nerve fiber/ganglionic cell layer. A thinning of these layers is also observed in NMOSD patients, where it is thought to be a consequence of optic neuritis. Neuromyelitis optica immunoglobulin G might target cellular processes of Müller cells and cause their loss of AQP4 reactivity, when AQP4-specific T cells open the blood-retina barrier in the outer plexiform layer. Patchy loss of AQP4 reactivity on Müller cells of NMOSD patients has been recently described. Cumulatively, our findings in experimental NMOSD suggest that both CD4+ T cell and antibody responses directed against AQP4 might play an important role in the pathogenesis of tissue destruction seen in NMOSD.

Aquaporin 4-specific T cells and NMO-IgG cause primary retinal damage in experimental NMO/SD.

Neuromyelitis optica/spectrum disorder (NMO/SD) is a severe, inflammatory disease of the central nervous system (CNS). In the majority of patients, it is associated with the presence of pathogenic serum autoantibodies (the so-called NMO-IgGs) directed against the water channel aquaporin 4 (AQP4), and with the formation of large, astrocyte-destructive lesions in spinal cord and optic nerves. A large number of recent studies using optical coherence tomography (OCT) demonstrated that damage to optic nerves in NMO/SD is also associated with retinal injury, as evidenced by retinal nerve fiber layer (RNFL) thinning and microcystic inner nuclear layer abnormalities. These studies concluded that retinal injury in NMO/SD patients results from secondary neurodegeneration triggered by optic neuritis.However, the eye also contains cells expressing AQP4, i.e., Müller cells and astrocytes in the retina, epithelial cells of the ciliary body, and epithelial cells of the iris, which raised the question whether the eye can also be a primary target in NMO/SD. Here, we addressed this point in experimental NMO/SD (ENMO) induced in Lewis rat by transfer of AQP4268-285-specific T cells and NMO-IgG.We show that these animals show retinitis and subsequent dysfunction/damage of retinal axons and neurons, and that this pathology occurs independently of the action of NMO-IgG. We further show that in the retinae of ENMO animals Müller cell side branches lose AQP4 reactivity, while retinal astrocytes and Müller cell processes in the RNFL/ganglionic cell layers are spared. These changes only occur in the presence of both AQP4268-285-specific T cells and NMO-IgG.Cumulatively, our data show that damage to retinal cells can be a primary event in NMO/SD.

Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord.

Neuromyelitis optica (NMO) is an acute inflammatory disease of the central nervous system (CNS) which predominantly affects spinal cord and optic nerves. Most patients harbor pathogenic autoantibodies, the so-called NMO-IgGs, which are directed against the water channel aquaporin 4 (AQP4) on astrocytes. When these antibodies gain access to the CNS, they mediate astrocyte destruction by complement-dependent and by antibody-dependent cellular cytotoxicity. In contrast to multiple sclerosis (MS) patients who benefit from therapies involving type I interferons (I-IFN), NMO patients typically do not profit from such treatments. How is I-IFN involved in NMO pathogenesis? To address this question, we made gene expression profiles of spinal cords from Lewis rat models of experimental neuromyelitis optica (ENMO) and experimental autoimmune encephalomyelitis (EAE). We found an upregulation of I-IFN signature genes in EAE spinal cords, and a further upregulation of these genes in ENMO. To learn whether the local I-IFN signature is harmful or beneficial, we induced ENMO by transfer of CNS antigen-specific T cells and NMO-IgG, and treated the animals with I-IFN at the very onset of clinical symptoms, when the blood-brain barrier was open. With this treatment regimen, we could amplify possible effects of the I-IFN induced genes on the transmigration of infiltrating cells through the blood brain barrier, and on lesion formation and expansion, but could avoid effects of I-IFN on the differentiation of pathogenic T and B cells in the lymph nodes. We observed that I-IFN treated ENMO rats had spinal cord lesions with fewer T cells, macrophages/activated microglia and activated neutrophils, and less astrocyte damage than their vehicle treated counterparts, suggesting beneficial effects of I-IFN.

Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS.

In neuromyelitis optica (NMO), astrocytes become targets for pathogenic aquaporin 4 (AQP4)-specific antibodies which gain access to the central nervous system (CNS) in the course of inflammatory processes. Since these antibodies belong to a T cell-dependent subgroup of immunoglobulins, and since NMO lesions contain activated CD4(+) T cells, the question arose whether AQP4-specific T cells might not only provide T cell help for antibody production, but also play an important role in the induction of NMO lesions. We show here that highly pathogenic, AQP4-peptide-specific T cells exist in Lewis rats, which recognize AQP4268-285 as their specific antigen and cause severe panencephalitis. These T cells are re-activated behind the blood-brain barrier and deeply infiltrate the CNS parenchyma of the optic nerves, the brain, and the spinal cord, while T cells with other AQP4-peptide specificities are essentially confined to the meninges. Although AQP4268-285-specific T cells are found throughout the entire neuraxis, they have NMO-typical "hotspots" for infiltration, i.e. periventricular and periaqueductal regions, hypothalamus, medulla, the dorsal horns of spinal cord, and the optic nerves. Most remarkably, together with NMO-IgG, they initiate large astrocyte-destructive lesions which are located predominantly in spinal cord gray matter. We conclude that the processing of AQP4 by antigen presenting cells in Lewis rats produces a highly encephalitogenic AQP4 epitope (AQP4268-285), that T cells specific for this epitope are found in the immune repertoire of normal Lewis rats and can be readily expanded, and that AQP4268-285-specific T cells produce NMO-like lesions in the presence of NMO-IgG.