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To evaluate a software simulating perfused liver volume from virtual selected embolization points on proximal enhanced cone-beam CT (CBCT) liver angiography data set by using selective CBCT as reference standard.Seventy-eight selective/proximal CBCT couples in 46 patients referred for intra-arterial liver treatment at two recruiting centers were retrospectively included. A reference selective volume (RSV) was calculated from the selective CBCT by manual segmentation and was used as a reference standard. The Virtual Perfusion Volume (VPV) was then obtained using Liver ASSIST Virtual Parenchyma software on proximal CBCT angiography using the same injection point as for selective CBCT. RSV and VPV were then compared as absolute, relative, and signed volumetric errors (ABSThe software was technically successful in automatically computing VPV in 74/78 cases (94.8%).On the 74 analyzed couples, median RSV was not significantly different from VPV (394 cc [196 - 640cc] and 391 cc [192 - 620cc] respectively, p=0.435).Median ABSPerfusion hepatic volumes simulated on proximal enhanced CBCT using the virtual parenchyma software are numerically and spatially similar to those manually obtained on selective CBCT.

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas’ primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology. Significance: Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti–PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799

International audience; Criteria based on measurements of lesion diameter at CT have guided treatment with historical therapies due to the strong association between tumor size and survival. Clinical experience with immune checkpoint modulators shows that editing immune system function can be effective in various solid tumors. Equally, novel immune-related phenomena accompany this novel therapeutic paradigm. These effects of immunotherapy challenge the association of tumor size with response or progression and include risks and adverse events that present new demands for imaging to guide treatment decisions. Emerging and evolving approaches to immunotherapy highlight further key issues for imaging evaluation, such as dissociated response following local administration of immune checkpoint modulators, pseudoprogression due to immune infiltration in the tumor environment, and premature death due to hyperprogression. Research that may offer tools for radiologists to meet these challenges is reviewed. Different modalities are discussed, including immuno-PET, as well as new applications of CT, MRI, and fluorodeoxyglucose PET, such as radiomics and imaging of hematopoietic tissues or anthropometric characteristics. Multilevel integration of imaging and other biomarkers may improve clinical guidance for immunotherapies and provide theranostic opportunities.

Immuno-Histo-Chemistry scoring of baseline tumor biopsies according to their DCB status.

Baseline characteristics of the patients treated.

Cytotoxic response in tumor biopsies of patients with No DCB upon combination treatment.

Baseline characteristics of the patients treated according to their DCB status.

Treatment and dose modifications in patients according to their DCB status.

Further descriptions of tumor immune infiltrates.

Adverse events emergent during treatment and related to experimental drugs by the investigators according to CTCAE Version 4.03.

Additional significant differences in circulating chemokines.

Gating strategy for flow cytometry analyses of T cells infiltration on tumor biopsies.

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas’ primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.Significance:Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti–PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies.This article is highlighted in the In This Issue feature, p. 799

Gene expression network analysis.

Angular error impact on accuracy according to tumor size and depth

Devices for direct intratumoral immunotherapy

Human intratumoral immunotherapy (HIT-IT) is under rapid development, with promising preliminary results and high expectations for current phase III trials. While outcomes remain paramount for patients and the referring oncologists, the technical aspects of drug injection are critical to the interventional radiologist to ensure optimal and reproducible outcomes. The technical considerations for HIT-IT affect the safety, efficacy, and further development of this treatment option. Image-guided access to the tumor allows the therapeutic index of a treatment to be enhanced by increasing the intratumoral drug concentration while minimizing its systemic exposure and associated on-target off-tumor adverse events. Direct access to the tumor also enables the acquisition of cancer tissue for sequential sampling to better understand the pharmacodynamics of the injected immunotherapy and its efficacy through correlation of immune responses, pathologic responses, and imaging tumor response. The aim of this article is to share the technical insights of HIT-IT, with particular consideration for patient selection, lesion assessment, image guidance, and technical injection options. In addition, the organization of a standard patient workflow is discussed, so as to optimize HIT-IT outcome and the patient experience.

Supplementary Figure 3: NF2 deleterious mutations and sensitivity to lorlatinib (corresponding to main Figure 4).

Purpose:Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setting.Experimental Design:Resistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel ALK compound mutations. Drug combinatory strategies were evaluated in vitro and in vivo to overcome lorlatinib resistance.Results:Diverse biological mechanisms leading to lorlatinib resistance were identified. Epithelial–mesenchymal transition (EMT) mediated resistance in two patient-derived cell lines and was susceptible to dual SRC and ALK inhibition. We characterized three ALK kinase domain compound mutations occurring in patients, L1196M/D1203N, F1174L/G1202R, and C1156Y/G1269A, with differential susceptibility to ALK inhibition by lorlatinib. We identified a novel bypass mechanism of resistance caused by NF2 loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors.Conclusions:This study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.

Supplementary Figure 4: NF2 inhibition of mTORC1 and its canonical pathway.

Intratumoral injection techniques

Supplementary figures legends

Supplementary Figure 1: EMT mediated lorlatinib resistance (corresponding to main Figure 2).

Supplementary Figure 2: ALK secondary mutations (corresponding to main Figure 3).

The purpose of this study was to evaluate the long-term outcomes of patients with centrally located renal cell carcinomas (RCC) measuring 3 cm or larger, treated by a standardized transarterial embolization protocol associated with percutaneous ablation.This retrospective study included 11 patients (73% male, mean age 73.4 ± 6.5 years) with RCC and contraindications for surgery. All patients underwent a single session combining transarterial embolization with iodized oil and subsequent thermal percutaneous ablation. Primary and secondary local tumor control were analyzed, defined as absence of any contrast enhancing nodular lesion in the treated area after a single or percutaneous re-treatment session, respectively.Mean tumor size was 3.5 ± 0.3 cm (range 3-4 cm) with a mean R.E.N.A.L. nephrometry score ((R)adius; (E)xophytic, endophytic properties; (N)earness to the collecting system; (A)nterior, posterior; (L)ocation relative to the polar line) of 8 ± 0.9 (range 7-9). Nearness to the collecting system was 4-7 mm in two patients (18%) and ≤ 4 mm in nine patients (82%). After a mean follow-up of 5.2 ± 2.5 years primary and secondary local tumor control rate were 82% and 100%, respectively. No change in serum creatinine levels and glomerular filtration rate was observed compared to pre-treatment values.A combined treatment of selective transarterial embolization and percutaneous ablation of large centrally located RCC ( 3 cm) is safe, feasible and can achieve excellent oncological long-term results. Larger prospective studies are needed.

The purpose of this study was to analyze the intrahepatic perfusion redistribution after embolization of hepatic arterial variants during percutaneous arterial port catheter placement as well as to investigate the treatment efficacy of intraarterial chemotherapy in perfusion redistribution-dependent compared to redistribution-independent liver areas.This retrospective study included 62 patients (67.7% males, mean age of 56 ± 12 years). A replaced left hepatic artery was encountered in 36/62 (58.1%), a replaced right hepatic artery in 19/62 (30.6%) and a replaced left and right hepatic artery in 7/62 of patients (11.3%), respectively. Subjective perfusion analysis was performed on digital subtracted angiography and computed tomography (CT)/cone-beam computed tomography (CBCT) images evaluating the visibility of the main, segmental and subsegmental branches of the embolized variant hepatic artery, re-perfused from intrahepatic arterial anastomoses. For objective perfusion analysis ROI measurements on CT/CBCT images were taken in the redistribution-dependent and redistribution-independent liver lobe. Response analysis according to RECIST 1.1 was separately calculated for the redistribution-dependent and redistribution-independent liver lobe.Intrahepatic reperfusion of the embolized variant hepatic artery was observed immediately after embolization with visualization of the subsegmental branches in 95.2% of patients. ROI measurements on CT/CBCT images (right lobe mean 76 ± 30.2 HU, left lobe mean 74.4 ± 30.5, p-value 0.88) did not show any differences. Treatment response after intraarterial chemotherapy did not differ between the redistribution-dependent and redistribution-independent liver lobes.Embolization of hepatic arterial variants during percutaneous arterial port catheter placement results in effective intrahepatic perfusion redistribution and does not compromise treatment efficacy of intraarterial chemotherapy in the redistribution-dependent liver lobe.

Purpose To investigate whether liver enhancing tumor burden (LETB) assessed at contrast-enhanced CT indicates early response and helps predict survival outcomes in patients with multifocal neuroendocrine liver metastases (NELM) after intra-arterial treatment. Materials and Methods This retrospective study included patients with NELM who underwent intra-arterial treatment with transarterial embolization (TAE) or chemoembolization (TACE) between April 2006 and December 2018. Tumor response in treated NELM was evaluated by using the Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST). LETB was measured as attenuation 2 SDs greater than that of a region of interest in the nontumoral liver parenchyma. Overall survival (OS); time to unTA(C)Eable progression, defined as the time from the initial treatment until the time when intra-arterial treatments were considered technically unfeasible, either not recommended by the multidisciplinary tumor board or until death; and hepatic and whole-body progression-free survival (PFS) were evaluated using multivariable Cox proportional hazards analyses, the Kaplan-Meier method, and log-rank test. Results The study included 119 patients (mean age, 60 years ± 11 [SD]; 61 men) who underwent 161 treatments. A median LETB change of -25.8% best discriminated OS (83 months in responders vs 51 months in nonresponders; P = .02) and whole-body PFS (18 vs 8 months, respectively; P < .001). A -10% LETB change best discriminated time to unTA(C)Eable progression (32 months in responders vs 12 months in nonresponders; P < .001) and hepatic PFS (18 vs 8 months, respectively; P < .001). LETB change remained independently associated with improved OS (hazard ratio [HR], 0.56), time to unTA(C)Eable progression (HR, 0.44), hepatic PFS (HR, 0.42), and whole-body PFS (HR, 0.47) on multivariable analysis. Neither RECIST nor mRECIST helped predict patient outcome. Conclusion Response according to LETB change helped predict survival outcomes in patients with NELM after intra-arterial treatments, with better discrimination than RECIST and mRECIST. Keywords: CT, Chemoembolization, Embolization, Abdomen/GI, Liver Supplemental material is available for this article. © RSNA, 2023.

Interventional radiology techniques provide excellent local tumor control for small tumors in various organs, but several limitations can hamper the oncological outcomes such as the tumor size or the number of lesions. Technical improvements, optimal patient selection and combination with systemic therapies, including immune checkpoint inhibitors, have been successfully developed to overcome these barriers. In this setting, chemotherapy and targeted therapies aim to diminish the tumor burden in addition to local treatments, while immunotherapies may have a synergistic effect in terms of mechanism of action on the tumor cell as well as the immune environment, with multiple treatment combinations being available. Finally, interventional Rrdiology treatments often increase tumor antigen exposure to the immune system, and thus stimulate a specific antitumor immune response that can act beyond the treated site. Notwithstanding their many benefits, combination treatment may also result in complications, the most feared may be auto-immune-related adverse events. In early studies, several combined therapies have shown promising levels of safety and efficacy, particularly in hepatocellular carcinoma. This review provides a comprehensive and up-to-date overview of results of combined therapies for primary and secondary liver malignancies. Recent advances and future perspectives will be discussed.

Interventional radiology techniques provide excellent local tumor control for small tumors in various organs, but several limitations can hamper the oncological outcomes such as the tumor size or the number of lesions. Technical improvements, optimal patient selection and combination with systemic therapies, including immune checkpoint inhibitors, have been successfully developed to overcome these barriers.In this setting, chemotherapy and targeted therapies aim to diminish the tumor burden in addition to local treatments, while immunotherapies may have a synergistic effect in terms of mechanism of action on the tumor cell as well as the immune environment, with multiple treatment combinations being available. Finally, interventional Rrdiology treatments often increase tumor antigen exposure to the immune system, and thus stimulate a specific antitumor immune response that can act beyond the treated site. Notwithstanding their many benefits, combination treatment may also result in complications, the most feared may be auto-immune-related adverse events.In early studies, several combined therapies have shown promising levels of safety and efficacy, particularly in hepatocellular carcinoma.This review provides a comprehensive and up-to-date overview of results of combined therapies for primary and secondary liver malignancies. Recent advances and future perspectives will be discussed.

Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as “adjuvants” to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner.

Background Several selective FGFR inhibitors have been developed for the treatment of FGFR-driven urothelial cancer, in particular erdafitinib which received FDA and EMA approval. Molecular mechanisms responsible for resistance to FGFR inhibitors have not been elucidated in urothelial cancer. Understanding these resistance mechanisms is crucial for the development of novel agents and treatment strategies. Methods We identified patients with metastatic urothelial cancer harboring FGFR mutations or rearrangements, treated with selective FGFR inhibitors in the MATCH-R (NCT02517892), MOSCATO (NCT01566019), STING-UNLOCK (NCT04932525), and CTC studies at Gustave Roussy. Post-progression tissue biopsies and circulating tumor DNA (ctDNA) were analyzed with whole exome sequencing and Illumina or FoundationOne assays, respectively. We generated Ba/F3 models containing FGFR3::TACC3 transcript with the FGFR3 kinase domain mutations detected in post-progression samples and exposed them to eight FGFR inhibitors (readouts: cell viability assays and Western blots). We established patient-derived xenografts (PDX) and cell lines to assess resistance mechanisms and perform pharmacological studies. Results Twenty-one patients with post-progression samples (n = 13 both tissue and ctDNA, n = 5 ctDNA only, n = 3 tissue only) were included in our study. The molecular driver was identified as FGFR3 mutations/fusions in 19 cases, whereas one FGFR4 mutation and one FGFR2 rearrangement were found in two patients. Patients progressed to erdafitinib (n = 14), futibatinib (n = 4) or pemigatinib (n = 3). Thirteen, six, and two patients experienced response, stable disease, and progression, respectively. At progression, we detected single mutations in the FGFR kinase domain in six (29%) patients (FGFR3 N540K, V553L, V553M, V555L, V555M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, L608V). Using Ba/F3 cells, we confirmed that the detected mutations conferred resistance to FGFR inhibitors. FGFR3 V553L, emerging in a patient treated with pemigatinib, was sensitive to erdafitinib and futibatinib. We detected alterations in the mTOR pathway in 11 (52%) patients (n = 5 TSC1/2, n = 5 PIK3CA, n = 1 NF2, n = 1 PTEN), with or without FGFR3 kinase domain mutations. In patient-derived models, erdafitinib combined with pictilisib was synergic in the presence of PIK3CA E545K, while erdafitinib-gefitinib combination overcame bypass resistance mediated by EGFR activation. Conclusions We detected a high frequency of FGFR kinase domain mutations at progression to selective FGFR inhibitors in urothelial cancer. Unlike FGFR2-driven cholangiocarcinoma, polyclonality of FGFR3 kinase domain mutations does not seem to be a hallmark of FGFR-driven urothelial cancer. The identification of off-target events and the preclinical validation sustain the potential clinical applicability of combinatorial treatment strategies. Citation Format: Francesco Facchinetti, Antoine Hollebecque, Floriane Braye, Damien Vasseur, Yoann Pradat, Rastislav Bahleda, Cédric Pobel, Ludovic Bigot, Olivier Déas, Juan-David Florez-Arango, Giorgia Guaitoli, Hayato Mizuta, David Combarel, Lambros Tselikas, Stefan Michiels, Sergey Nikolaev, Jean-Yves Scoazec, Santiago Ponce-Aix, Benjamin Besse, Ken A. Olaussen, Yohann Loriot, Luc Friboulet. Resistance to selective FGFR inhibitors in FGFR-driven urothelial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3458.

Introduction: In the last 20 years, the advances in molecular oncology and cancer genetics allowed the identification of an increasing number of actionable oncogenic drivers and the development and clinical use of specific inhibitors. Despite these successes, it is now well established that tumour cells adapt and develop acquired resistance. It is crucial to understand these mechanisms of acquired resistance to develop overcoming therapeutic strategies. At Gustave Roussy, a prospective clinical trial MATCH-R (NCT02517892) is conducted to study the acquired resistance mechanisms and to find new therapeutic approaches for patients.. In parallel, of genetics analysis from patients biopsies, we develop Patient Derived Xenograft (PDX) to deepen our understanding of the resistance mechanism and to investigate new therapeutic approaches. Material and Method: Fresh tumor biopsy specimens were obtained prospectively from patients through a prospective single-institution clinical trial (MATCH-R, NCT02517892). Patient derived xenografts (PDX) in NOD Scid Gamma (NSG) mice as well as patient derived organoids from PDX (PDXO) and Patient derived cell lines were developed and characterized. Extensive molecular profiling including whole exome sequencing (WES), RNA sequencing (RNAseq) and immunohistochemistry were performed on human samples; PDX; Patient derived cells lines and PDXO. Results and Discussion: As of November 2022, 145 PDX models have been successfully obtained from 371 biopsies (global take rate of 39%). Our focus is the development of models from different cohorts: Androgen receptor inhibitors in castration-resistant prostate cancer, (18 PDX), ALK inhibitors in lung cancers (16 PDX including 3 post brigatinib, 7 post Lorlatinib and 6 Alectinib), EGFR inhibitors in lung cancers (33 PDX includind 24 post osimertinib), FGFR inhibitors in urothelial carcinoma and cholangiocarcinoma (29 PDX including 14 post erdafitinib, 4 post pemigatinib, 4 post futibatinib) and KRAS inhibitors in lung cancer and pancreatic cancers (20 PDX). The PDX models recapitulate the genetics, the phenotype and the pharmacology of the original biopsies. Novel mechanisms of resistance to tyrosine kinase inhibitors (TKI) in solid tumors were identified. Adaptive treatment with novel TKI or combinatorial strategies were evaluated to restore the sensitivity in PDX (readout: mean tumor growth). These results confirmed that PDX models are crucial to study the resistance mechanism and to develop new therapeutic strategies. Conclusion: Overall, the MATCH-R study provides a unique preclinical platform to identify resistance mechanisms to innovative therapies and to develop next generation therapeutic strategies. Citation Format: Ludovic Bigot, Catline Nobre, Francesco Facchinetti, Loic Poiraudeau, Floriane Braye, Jonathan Sabio, Naoual Mensourri, Olivier Deas, Claudio Nicotra, Maud Ngo-Camus, Lambros Tselikas, Jean Yves Scoazec, Karim Fizazi, Siantiago Ponce, Benjamin Besse, Luc Friboulet, Yohann Loriot. MatchR a preclinical platform of models resistant to innovative therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4664.

Systemic immunotherapies such as immune checkpoint blockade targeted at PD(L)1 and CTLA4 have demonstrated their ability to provide durable tumor responses and long-term overall survival benefits for some patients in several solid tumor types. However, a majority of patients remain resistant to these treatments and a significant proportion of them develop severe autoimmune and inflammatory adverse events. Preclinical studies have demonstrated that intratumoral injections of immunostimulatory products (oncolytics, pattern recognition receptor agonists,…) that are able to trigger type I IFN release and enhance tumor antigen presentation on immune cells could generate a strong antitumor immunity and overcome the resistance to systemic immune checkpoint blockade therapies. The intratumoral immunotherapy strategies that are currently in clinical development offer a unique therapeutic and exploratory setting to better understand the immune contexture across tumor lesions of patients with metastatic cancer. Also these local therapeutic products could turn cold tumors into hot and improve the response rates to cancer immunotherapies while diminishing their systemic exposure and toxicities. Intratumoral immunotherapies could prime or boost the immunity against tumors and therefore radically change the combinatorial therapeutic strategies currently pursued for metastatic and local cancers to improve their long-term survival. We aimed to review and discuss the scientific rationale for intratumoral immunotherapy, the challenges raised by this strategy in terms of drug development within clinical trials and the current state-of-the-art regarding the clinical practice of this innovative approach.

Curative treatment of oligometastatic pulmonary disease aims at eradication of all metastases. Radiofrequency ablation (RFA) has been shown to be an efficient method and the frequency of local tumor progression (LTP) should be minimized. The objective of this study was to determine the morphological and treatment-related risk factors for LTP after RFA of pulmonary metastases. All patients treated with RFA for pulmonary metastases from 2002 to 2014 were reviewed. All LTPs from 2011 to 2014 were individually matched on the basis of tumor size, number, and histology. In total, 48 LTPs and 112 controls were blindly analyzed for morphological factors including vicinity of bronchus and vessels as well as treatment-related factors such as the size of the ablation zone and ablation margins. In the simple regression analysis, the significant predictive variables were ≤ 5-mm distance to a large bronchus (OR = 4.94; p = 0.0095) or large vessel (OR = 7.09; p 0.36 (OR = 13.83; p = 0.013). In the multiple regression model, only a minimal ablation margin ≤ 5 mm remained a significant risk factor for LTP. Only the minimal ablation margin remains significant in the multiple regression analysis; the other factors are presumably surrogates of an insufficient ablation margin. Improvement of lung RFA outcomes can probably be obtained by immediate post RFA evaluation of ablation margins to ensure a minimal ablation margin of at least 5 mm. • A distance 5 mm after pulmonary RFA is associated with significantly less local tumor progression and should be looked for at the end of treatment session before needle removal in order to decrease local tumor progression. • Tumor location, pleural contact, occurrence of intra-alveolar hemorrhage, pulmonary atelectasis, and pneumothorax are not associated with an increased risk of local tumor progression.

International audience; Hepatic arterial infusion (HAI) of oxaliplatin allows greater liver tumour drug exposure compared to systemic infusion. However, the therapeutic index of HAI oxaliplatin remains poor. Using Pickering emulsion technology, we developed a platform able to provide sustained releases of oxaliplatin. The goal of this study was to evaluate the pharmacokinetic advantages of sustained-HAI oxaliplatin over HAI using a preclinical animal tumour model. Injections of 0.6 mg oxaliplatin in 20 min were selectively done in left hepatic arteries of 20 rabbits bearing a VX2 liver tumour in the middle left-lobe, using HAI (n = 10) or sustained-HAI (n = 10). In each group, half of the rabbits were sacrificed at 24 h and half at 72 h. Mass spectrometry was used to quantify drug pharmacokinetics in blood and oxaliplatin concentrations in tumour tissues, right- and middle left-liver lobes, spleen and lung. Compared to HAI, sustained-HAI of oxaliplatin resulted in lower plasmatic peak (Cmax: 275 ± 41 vs. 416 ± 133 ng/mL, p = 0.02) and higher concentration in the tumour at 24 h (2118 ± 2107 vs. 210 ± 93 ng/g, p = 0.008). After HAI, oxaliplatin concentration in tumours was significantly higher than in lung at 24 h (p = 0.03) but no other difference was found between oxaliplatin concentrations in tumours and in liver lobes, spleen or lung, neither at 24 h nor at 72 h. On the opposite, sustained-HAI resulted in higher concentrations of oxaliplatin in tumour compared to oxaliplatin concentrations in the middle left lobe (163 ± 86 ng/g at 24 h, p = 0.01, and 90 ± 15 ng/g at 72 h, p = 0.04), right lobe (174 ± 112 ng/g at 24 h, p = 0.01, and 112 ± 35 ng/g, p = 0.04 at 72 h), spleen (142 ± 21 ng/g at 24 h, p = 0.01, and 98 ± 12 ng/g at 72 h, p = 0.04), and lung (85 ± 11 ng/g at 24 h, p = 0.01, and 52 ± 4 ng/g at 72 h, p = 0.03). Sustained-HAI improves the therapeutic index of HAI oxaliplatin and offers a great potential for patients suffering from unresectable colorectal liver metastases or hepatocellular carcinoma.

To evaluate the feasibility and safety of percutaneous transpedicular fixation by PEEK polymer implants and cementoplasty for vertebral compression fracture (VCF). From February 2019 to December 2019, 6 consecutive patients (3 men and 3 women; mean age 55 ± 8 years; range 40–64 years) who had percutaneous transpedicular fixation with cementoplasty for the treatment of VCF (5 tumor lesions, 1 traumatic) were included. The procedure duration, length of hospital stay, and complications were reported. Visual analog scale (VAS) and the Oswestry disability index (ODI) for pain and disability were assessed before and 2 months after the procedure. The mean procedure duration was 74 ± 47 min (range 20–140 min). The median length of hospital stay was 3 days (range 2–63) after the procedure. Only minor adverse events were reported (4 asymptomatic cement leakages) but no severe complications. No cases of procedural site fracture during follow-up were noted (median 198 days; range 78–238 days). The mean VAS score decreased from 6.2 ± 1.8 mm (median 6 mm; range 4–9 mm) before the procedure to 1.7 ± 2.1 mm (median 1; range 0–5 mm) after the procedure. The ODI decreased from 36 ± 14% (range 18–54%) before the procedure to 23 ± 10% (range 11–30%) at 2-months follow-up. Percutaneous transpedicular fixation of VCF by PEEK implants with cementoplasty appears feasible and safe.

International audience; BACKGROUND: All randomised phase 3 studies of selective internal radiation therapy for advanced hepatocellular carcinoma published to date have reported negative results. However, these studies did not use personalised dosimetry. We aimed to compare the efficacy of a personalised versus standard dosimetry approach of selective internal radiation therapy with yttrium-90-loaded glass microspheres in patients with hepatocellular carcinoma.METHODS: DOSISPHERE-01 was a randomised, multicentre, open-label phase 2 trial done at four health-care centres in France. Patients were eligible if they were aged 18 years or older and had unresectable locally advanced hepatocellular carcinoma, at least one measurable lesion 7 cm or more in size, a hepatic reserve of at least 30% after selective internal radiation therapy, no extrahepatic spread (other than to the lymph nodes of the hilum, with a lesion 5% of patients) grade 3 or higher adverse events were ascites (one [3%] patient who received personalised dosimetry vs two [10%] patients who received standard dosimetry), hepatic failure (two [6%] vs none), lymphopenia (12 [34%] vs nine [43%]), increased aspartate aminotransferase concentrations (three [9%] vs two [10%]), increased alanine aminotransferase concentrations (three [9%] vs none), anaemia (two [6%] vs one [5%]), gastrointestinal haemorrhage (none vs two [10%]), and icterus (none vs two [10%]). One treatment-related death occurred in each group.INTERPRETATION: Compared with standard dosimetry, personalised dosimetry significantly improved the objective response rate in patients with locally advanced hepatocellular carcinoma. The results of this study suggest that personalised dosimetry is likely to improve outcomes in clinical practice and should be used in future trials of selective internal radiation therapy. FUNDING: Biocompatibles UK, a Boston Scientific Group company.

Background Prophylactic image-guided procedures performed by interventional radiologists for impending pathologic fractures are becoming more pertinent, as patients with metastatic cancer have extended overall survival because of advanced therapies. Purpose To evaluate the efficacy, safety, and palliative durability of collimated-beam CT-guided percutaneous fixation with internal cemented screws (FICS) for impending pathologic fractures of the femoral neck. Materials and Methods This single-institute retrospective study examined all patients with metastatic cancer treated between February 2010 and October 2019 with collimated-beam CT-guided percutaneous FICS procedures for preventive consolidation of impending femoral neck pathologic fractures. The short-term palliative efficacy was assessed through comparison of visual analog scale (VAS) scores before and 1 month after FICS. A review of cross-section imaging and clinic reports identified any procedural complications. Long-term consolidation efficacy was defined as the absence of any screw dislodgement or development of a pathologic fracture at completion of the study. The Wilcoxon test was used for the mean comparison of paired nonparametric variables. Results Sixty-one consecutive patients (mean age, 59 years ± 11 [standard deviation]; 35 women) underwent preventive FICS for consolidation of impending pathologic femoral neck fracture with a mean follow-up of 533 days ± 689. Two patients died of cancer within the first month. Complications were limited to three self-resolving hematomas. The mean VAS score decreased 1 month after FICS from 4.2 ± 3.2 to 1.8 ± 2.0 (P < .001). The long-term consolidation efficacy was 92% (54 of 59 patients), with three of 59 patients (5%) subsequently developing fractures despite FICS and an additional two of 59 patients (3%) with durable FICS undergoing definitive total hip arthroplasty surgery because of local tumor progression. Conclusion Percutaneous fixation with internal cemented screws as performed by the interventional radiologist is a safe nonsurgical treatment that provides an effective palliative result and durable prevention for impending pathologic fractures of the femoral neck. © RSNA, 2020 Online supplemental material is available for this article.

Objective: The recommended first-line treatment for low-tumor-burden ACC (stage IVa ACC) not amenable to radical resection is mitotane in association with loco-regional treatments (LRs). The aim of this study was to determine the patient population that would benefit the most from LR. Materials and methods: This retrospective monocentric expert center chart review study was performed from 2008 to 2021 and included stage IVa patients (≤2 tumoral organs) treated with LR (either radiotherapy, surgery, or interventional radiology). The primary endpoint was disease control (DC). Correlations between DC, time to systemic chemotherapy (TTC), overall survival (OS), and tumor characteristics were analyzed using Kaplan–Meier survival analysis and Cox’s proportional hazards regression model for multivariate analysis. Results: Thirty-four women (57%) and 26 men with a median age of 48.1 years (IQR: 38.3–59.8) were included. One hundred and nine LRs were performed, with a median of 2 (IQR: 1–3) per patient. DC was achieved in 40 out of 60 patients (66.7%). Patients with DC had a significantly longer TTC (HR: 0.27, p < 0.001) and OS (HR: 0.22, p < 0.001). Patients with less than or equal to 5 metastases (HR: 6.15 (95% CI: 1.88–20.0), p = 0.002) or a maximum metastasis diameter below 3 cm had higher rates of DC (HR: 3.78 (95% CI: 1.09–13.14), p = 0.035). Conclusion: stage IVa ACC patients with ≤5 metastases or a maximum metastasis diameter below 3 cm had favorable responses to LR. We propose the name oligometastatic ACC for this subgroup of patients.

The purpose of this study was to evaluate the safety and efficacy of transarterial chemoembolization (TACE) combined with percutaneous thermal ablation in patients with liver metastases 3 cm in diameter or larger.This retrospective study included 39 patients with a total of 46 liver metastases treated. There were 14 men and 25 women, with a mean age of 55 ± 13.3 (SD) (age range: 28-77 years). All patients were treated with a combination of TACE and thermal ablation in a single session. Primary outcome was local tumor progression. Secondary outcomes were procedure related complications and systemic disease progression.Mean tumor size was 3.6 ± 0.6 (SD) cm (range: 3-5 cm). Conventional TACE was performed in 32 liver metastases (32/46; 70%) and drug-eluting beads-TACE in 14 liver metastases (14/46; 30%) followed by radiofrequency ablation in 34 (34/46; 74%), microwave ablation in 11 (11/46; 24%) and cryoablation in one (1/46; 2%) metastasis. Four grade 2 (4/39; 10%) complications were observed. After a mean follow up of 31.9 ± 26.1 (SD) months (range: 2-113 months) overall local tumor progression rate was 15% (7/46). Local tumor progression rate at 12 months was 13% (6/46). Overall systemic disease progression was seen in 29 patients (29/39; 74%) with a systemic disease progression rate at 12 months of 59% (23/39).Treatment of large liver metastases with TACE and thermal ablation in a single session is safe and achieves high local control rate.

Background: Interventional radiology plays a major role in oncology both for curative and palliative treatment, but few reports address post-procedural pain. The purpose of this study was to quantify postoperative pain after interventional radiology procedures in oncology and to identify major pain-associated pre and intraoperative factors. Methods: From 2015 to 2019, all patients treated with interventional radiology were included retrospectively in a cohort study. Anesthetic protocols were standardized by the type of radiological procedure. Demographic data, preoperative treatments, analgesic agents, pain score levels, and morphine consumption from the post-anesthesia care unit (PACU) to hospital discharge were collected from databases. In an additional case-control study, patients reporting strong or intolerable pain in PACU were compared to those with no pain. Matching to control cases was based on the type of intervention, sex, and age. Results: From 4411 procedures, severe pain in PACU was more frequent in women (p < 0.04) and the youngest patients (p < 0.0001), after general anesthesia (p < 0.0001). Higher pain levels were associated with certain procedures, such as arterial embolization, limb cementoplasty, osteosynthesis, and abdominal tumor ablation, and when the intervention duration exceeded 160 min (p = 0.038). In the cohort study, high-dose remifentanil (≥0.055 µg/kg/min) was a risk factor for post-procedural high pain levels (p < 0.001). Intraoperative ketoprofen was associated with a decrease in high pain level incidence (p < 0.0001). Severe pain in PACU was a risk factor for severe pain in wards from day 0 until discharge. Conclusion: Severe pain depends on the type and duration of interventional radiology, type of anesthesia, and preoperative use of opiates. Limiting doses of remifentanil and injecting intraoperative analgesics, especially ketoprofen, may reduce the incidence of post-intervention severe pain.

To establish national reference levels (RLs) in interventional procedures under CT guidance as required by the 2013/59/Euratom European Directive. Seventeen categories of interventional procedures in thoracic, abdominopelvic, and osteoarticular specialties (percutaneous infiltration, vertebroplasty, biopsy, drainage, tumor destruction) were analyzed. Total dose length product (DLP), number of helical acquisitions (NH), and total DLP for helical, sequential, or fluoroscopic acquisitions were recorded for 10 to 20 patients per procedure at each center. RLs were calculated as the 3rd quartiles of the distributions and target values for optimization process (TVOs) as the median. RLs and TVOs were compared with previously published studies. Results on 5001 procedures from 49 centers confirmed the great variability in patient dose for the same category of procedures. RLs were proposed for the DLPs and NHs in the seventeen categories. RLs in terms of DLP and NH were 375 mGy.cm and 2 NH for spinal or peri-spinal infiltration, 1630 mGy.cm and 3 NH for vertebroplasty, 845 mGy.cm and 4 NH for biopsy, 1950 mGy.cm and 8 NH for destruction of tumors, and 1090 mGy.cm and 5 NH for drainage. DLP and NH increased with the complexity of procedures. This study was the first nationwide multicentric survey to propose RLs for interventional procedures under CT guidance. Heterogeneity of practice in centers were found with different levels of patient doses for the same procedure. The proposed RLs will allow imaging departments to benchmark their practice with others and optimize their protocols. • National reference levels are proposed for 17 categories of interventional procedures under CT guidance. • Reference levels are useful for benchmarking practices and optimizing protocols. • Reference levels are proposed for dose length product and the number of helical acquisitions.

To discuss the pivotal role of Interventional radiology (IR) for the management of colorectal liver metastases (CRLM). IR has three main objectives for the treatment of CRLM: Radiofrequency ablation (RFA) is the most reported percutaneous ablation technique and provides high local control rates that exceed 90% for small metastases (

Purpose To evaluate microwave ablation (MWA) algorithms, comparing pulsed and continuous mode in an in vivo lung tumor mimic model Materials and methods A total of 43 lung tumor-mimic models of 1, 2 or 3 cm were created in 11 pigs through an intra-pulmonary injection of contrast-enriched minced muscle. Tumors were ablated under fluoroscopic and 3D-CBCT-guidance using a single microwave antenna. Continuous (CM) and pulsed mode (PM) were used. According to tumor size, 3 different algorithms for both continuous and pulsed mode were used. The ablation zones were measured using post-procedural 3D-CBCT and on pathologic specimens. Results Two radiologists measured the ablation zones on CBCT and they significantly correlated with macroscopic and microscopic pathological findings: r = 0.75 and 0.74 respectively (p

Many intratumoural (IT) immunotherapies are currently developed in the clinic with the aim of overcoming primary and secondary resistance and/or to limit on-target/off-tumour toxicities of immune checkpoint targeted therapies. This study aimed to describe the feasibility, safety and efficacy of IT immunotherapy treatments.This retrospective single-centre study included the first 100 consecutive patients enrolled in Gustave Roussy's Human IntraTumoral-ImmunoTherapy (HIT-IT) program. Patient characteristics, target description, image guidance, safety and response according to iRECIST (Response Evaluation Criteria in Solid Tumours for immunotherapy trials) were recorded. Predictive factors of complications and responses were analysed. Survival was also reported.From 09/2015 to 05/2020, 100 patients had 115 tumours injected during 423 treatment cycles. Most frequent primary tumour arose from the skin (n = 49), digestive track (n = 4) or head and neck (n = 8). Injected tumours' mean diameter was 37 ± 23 mm, and a median number of 4 IT injections per patient (interquartile range:3-5) were performed. Targeted tumours for IT injections were superficial lymph nodes (36.5%), subcutaneous lesions (25.2%), liver tumours (20.9%) and others (17.4% including tumour sites such as deep lymph nodes or lung). Most patients (72%) received systemic immunotherapy in combination with HIT-IT. Procedure- and drug-related adverse events (AEs) occurred in 11.3% and 33.3% of the treatment cycles, respectively. Only 3 procedure-related AEs were grade-3 (0.7%); and no grade-4 or 5 occurred. Among all cycles, 7 grade-3 and 1 grade-5 drug-related AEs were reported. Complete and partial responses were achieved for 5% and 18% of patients, respectively, while stable disease was the best response for 11%. Patients receiving HIT-IT as a 1st-line treatment (24%), or not previously pre-treated with immunotherapy (53%) responded better, p = 0.001 and p = 0.004, respectively. From 1st cycle of IT, 12-month overall progression-free survival and overall survival were 21% (14-31%) and 57% (47-68%), respectively.This retrospective study, conducted on patients with cancer and treated within clinical trials at Gustave Roussy, demonstrates the feasibility and safety of the IT immunotherapy strategy.