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Simple Summary Interventional oncology provides minimally invasive alternatives to many traditional medical and surgical treatments, offering a potential cure, control, or palliative care for many types of cancer patients. The aim of this article is to comprehensively review new indications for locoregional interventional oncology treatments and summarize the expert discussion and report from the "MIOLive Meets SIO" (Society of Interventional Oncology) session during the last Mediterranean Interventional Oncology Live congress held in Rome, Italy. Interventional oncology (IO) employs image-guided techniques to perform minimally invasive procedures, providing lower-risk alternatives to many traditional medical and surgical therapies for cancer patients. Since its advent, due to rapidly evolving research development, its role has expanded to encompass the diagnosis and treatment of diseases across multiple body systems. In detail, interventional oncology is expanding its role across a wide spectrum of disease sites, offering a potential cure, control, or palliative care for many types of cancer patients. Due to its widespread use, a comprehensive review of the new indications for locoregional procedures is mandatory. This article summarizes the expert discussion and report from the "MIOLive Meet SIO" (Society of Interventional Oncology) session during the last MIOLive 2022 (Mediterranean Interventional Oncology Live) congress held in Rome, Italy, integrating evidence-reported literature and experience-based perceptions. The aim of this paper is to provide an updated review of the new techniques and devices available for innovative indications not only to residents and fellows but also to colleagues approaching locoregional treatments.

In a 51-year-old woman affected by breast cancer, hepatic recurrence of disease was managed by concurrent Y-90-labeled glass microsphere embolization (transarterial radioembolization) and radiofrequency thermoablation. Intention-to-treat target, candidate to radioembolization, was in the IV hepatic segment; another lesion, managed with radiofrequency thermoablation, was in the VI-VII hepatic segment. Concomitant correction of a duodenocephalopancreatic shunting was performed as well. Thermoablation did not interfere with distribution of Tc-99m-macroaggregated albumin and Y-90-labeled microspheres to the target and healthy liver. At our knowledge, this is the first report that combines 2 locoregional procedures in different hepatic segments on the same day.

CRUE-CSIC (Acuerdos Transformativos 2022), Embolization with microspheres is a therapeutic strategy based on the selective occlusion of the blood vessels feeding a tumor. This procedure is intraarterially performed in the clinical setting for the treatment of liver cancer. The practice has evolved over the last decade through the incorporation of drug loading ability, biodegradability and imageability with the subsequent added functionality for the physicians and improved clinical outcomes for the patients. This review highlights the evolution of the embolization systems developed through the analysis of the marketed embolic microspheres for the treatment of malignant hepatocellular carcinoma, namely the most predominant form of liver cancer. Embolic microspheres for the distinct modalities of embolization (i.e., bland embolization, chemoembolization and radioembolization) are here comprehensively compiled with emphasis on material characteristics and their impact on microsphere performance. Moreover, the future application of the embolics under clinical investigation is discussed along with the scientific and regulatory challenges ahead in the field., Ministerio de Ciencia e Innovación (MICINN), Universidad Complutense de Madrid/Banco de Santander, Depto. de Farmacia Galénica y Tecnología Alimentaria, Fac. de Farmacia, TRUE, pub

Selective internal radiation therapy (SIRT) is part of the treatment strategy of liver tumors. SIRT can be performed using resin or glass microspheres, demonstrating different chemico-physical and radioactive properties. Post therapy imaging using 90Y PET/CT can evaluate the deposition of the tumor-absorbed dose and predict the patient outcome. 90Y PET/CT can also precisely evaluate the heterogeneous distribution of the absorbed dose within the tumor by calculating a equivalent uniform dose (EUD). Tumor EUD is strongly correlated with survival of patients and reunifies the absorbed doses between resin and glass microspheres as well as those from external radiation beam therapy. Moreover, pre-therapy imaging using 99mTc macroaggregated albumin (MAA) can optimize the activity planning, predicting with high accuracy the absorbed dose to the healthy liver. Furthermore, the tumor targeting can be optimized using a specific catheter during the arteriography, named antireflux catheter (ARC). Using ARC, the absorbed dose can be significantly increased in neuroendocrine and HCC tumors, hence, increasing the tumor control probability., (MED - Sciences médicales) -- UCL, 2022

Transarterial radioembolization (TARE) is a locoregional radiopharmaceutical therapy based on the delivery of radioactive 90Y microspheres to liver tumors. The importance of personalized dosimetry to make TARE safer and more effective has been demonstrated in recent clinical studies, stressing the need for quantification of the dose-response relationship to ultimately optimize the administered activity before treatment and image it after treatment. 90Y dosimetric studies are challenging because of the lack of accurate and precise methods but are best realized with PET combined with Monte Carlo simulations and other image modalities to calculate a segmental dose distribution. The aim of this study was to assess the suitability of imaging 90Y PET patients with the total-body PET/CT uEXPLORER and to investigate possible improvements in TARE 90Y PET-based dosimetry. The uEXPLORER is the first commercially available ultra-high-resolution (171 cps/kBq) total-body digital PET/CT device with a 194-cm axial PET field of view that enables the whole body to be scanned at a single bed position. Methods: Two PET/CT scanners were evaluated in this study: the Biograph mCT and the total-body uEXPLORER. Images of a National Electrical Manufacturers Association (NEMA) image-quality phantom and 2 patients were reconstructed using our standard clinical oncology protocol. A late portal phase contrast-enhanced CT scan was used to contour the liver segments and create corresponding volumes of interest. To calculate the absorbed dose, Monte Carlo simulations were performed using Geant4 Application for Tomographic Emission (GATE). The absorbed dose and dose-volume histograms were calculated for all 6 spheres (diameters ranging from 10 to 37 mm) of the NEMA phantom, the liver segments, and the entire liver. Differences between the phantom doses and an analytic ground truth were quantified through the root mean squared error. Results: The uEXPLORER showed a higher signal-to-noise ratio at 10

BackgroundExtrahepatic disease progression limits clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Trifluridine and tipiracil (TAS-102) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer.MethodsSequential lobar TARE using 90Y resin microspheres in combination with TAS-102 in 28-day cycles were used to treat adult patients with bilobar liver-dominant chemo-refractory mCRC according to 3 + 3 dose escalation design with a 12-patient dose expansion cohort. Study objectives were to establish safety and determine maximum tolerated dose (MTD) of TAS-102 in combination with TARE.ResultsA total of 21 patients (14 women, 7 men) with median age of 60 years were enrolled. No dose limiting toxicities were observed. Treatment related severe adverse events included cytopenias (10 patients, 48%) and radioembolization-induced liver disease (2 patients, 10%). Disease control rate in the liver lobes treated with TARE was 100%. Best observed radiographic responses were partial response for 4 patients (19%) and stable disease for 12 patients (57%).ConclusionsThe combination of TAS-102 and TARE for patients with liver-dominant mCRC is safe and consistently achieves disease control within the liver.Trial registrationClinicalTrials.gov identifier NCT02602327 (first posted 11/11/2015).

Purpose: To compare the treatment response and progression-free survival (PFS) in advanced hepatocellular carcinoma (HCC) patients who received sorafenib treatment either alone or combined with radioembolization (RE). Methods: Follow-up images of the patients treated within a multicenter phase II trial (SORAMIC) were assessed by mRECIST. A total of 177 patients (73 combination arm [RE + sorafenib] and 104 sorafenib arm) were included in this post-hoc analysis. Response and progression characteristics were compared between treatment arms. Survival analyses were done to compare PFS and post-progression survival between treatment arms. Multivariate Cox regression analysis was used to compare survival with factors known to influence PFS in patients with HCC. Results: The combination arm had significantly higher objective response rate (61.6% vs. 29.8%, p < 0.001), complete response rate (13.7% vs. 3.8%, p = 0.022), and a trend for higher disease control rate (79.2% vs. 72.1%, p = 0.075). Progression was encountered in 116 (65.5%) patients and was more common in the sorafenib arm (75% vs. 52.0%, p = 0.001). PFS (median 8.9 vs. 5.4 months, p = 0.022) and hepatic PFS were significantly better in the combination arm (9.0 vs. 5.7 months, p = 0.014). Multivariate analysis confirmed the treatment arm as an independent predictor of PFS. Conclusion: In advanced HCC patients receiving sorafenib, combination with RE has an additive anticancer effect on sorafenib treatment resulting in a higher and longer tumor response. However, the enhanced response did not translate into prolonged survival. Better patient selection and superselective treatment could improve outcomes after combination therapy.

Purpose: Gadoxetic acid uptake on hepatobiliary phase MRI has been shown to correlate with ß-catenin mutation in patients with HCC, which is associated with resistance to certain therapies. This study aimed to evaluate the prognostic value of gadoxetic acid uptake on hepatobiliary phase MRI in patients with advanced HCC receiving sorafenib. Methods: 312 patients with available baseline hepatobiliary phase MRI images received sorafenib alone or following selective internal radiation therapy (SIRT) within SORAMIC trial. The signal intensity of index tumor and normal liver parenchyma were measured on the native and hepatobiliary phase MRI images, and relative tumor enhancement higher than relative liver enhancement were accepted as high gadoxetic acid uptake, and its prognostic value was assessed using univariate and multivariate Cox proportional hazard models. Results: The median OS of the study population was 13.4 (11.8-14.5) months. High gadoxetic acid uptake was seen in 51 (16.3%) patients, and none of the baseline characteristics was associated with high uptake. In univariate analysis, high gadoxetic acid uptake was significantly associated with shorter overall survival (10.7 vs. 14.0 months, p = 0.005). Multivariate analysis confirmed independent prognostic value of high gadoxetic acid uptake (HR, 1.7 [1.21-2.3], p = 0.002), as well as Child-Pugh class (p = 0.033), tumor diameter (p = 0.002), and ALBI grade (p = 0.015). Conclusion: In advanced HCC patients receiving sorafenib (alone or combined with SIRT), high gadoxetic acid uptake of the tumor on pretreatment MRI, a surrogate of ß-catenin mutation, correlates with shorter survival. Gadoxetic acid uptake status might serve in treatment decision-making process.

[ES] El objetivo del presente Trabajo Final de Máster (TFM) es realizar un estudio dosimétrico de un tratamiento de braquiterapia hepática que emplea microesferas de Y-90 mediante simulación empleando el método de Monte Carlo. Si bien, un tratamiento de braquiterapia consiste en la introducción de la fuente en el interior del tumor, en concreto, para los carcinomas hepáticos, se emplea la radioembolización que consiste en la introducción de dichas semillas mediante la arteria hepática. Por ello, es importante conocer la dosis exacta que recibe el hígado, así como otros órganos colindantes que se pueden ver vascularmente afectados como es el caso del pulmón o el tracto gastrointestinal. Para ello, se emplea el modelo anatómico 3D distribuido recientemente por la Comisión Internacional de Protección Radiológica (ICRP) conocido como Fantoma Computacional de Referencia de Tipo de Malla (MRCP). Una vez segmentado el maniquí, se simula el tratamiento con el método de Monte Carlo, haciendo uso del código MCNP, introduciendo una fuente de Y-90 en el interior del hígado, así como todas las especificaciones de la física del transporte de fotones y electrones necesaria para la simulación. Como resultado, se obtiene la dosis que recibe el tumor del hígado, así como cada órgano colindante en un tratamiento de estas características. Se comprueba, además, que las dosis recibidas son seguras y se ajustan con los resultados empíricos. Con ello se demuestra que este método de simulación puede resultar adecuado para planificar tratamientos de braquiterapia obteniendo resultados fiables en un tiempo de computación asequible., [EN] The objective of this Master's Final Project (TFM) is to carry out a dosimetric study of a liver brachytherapy treatment that uses Y-90 microspheres by simulation using the Monte Carlo method. Although, a brachytherapy treatment consists of the introduction of the source into the tumor, in particular, for liver carcinomas, radioembolization is used, which consists of the introduction of these seeds through the hepatic artery. Therefore, it is important to know the exact dose received by the liver, as well as other adjoining organs that may be vascularly affected as is the case of the lung or the gastrointestinal tract. To do this, the 3D anatomical model recently distributed by the International Commission on Radiological Protection (ICRP) known as Mesh Type Reference Computational Fantoma (MRCP) is used. Once the mannequin is segmented, the treatment is simulated with the Monte Carlo method, making use of the MCNP code, introducing a Y-90 source inside the liver, as well as all the specifications of the physics of photon and electron transport necessary for the simulation. As a result, the dose received by the liver tumor is obtained, as well as each adjoining organ in a treatment of these characteristics. It is also verified that the doses received are safe and are adjusted with the empirical results. This demonstrates that this simulation method can be suitable for planning brachytherapy treatments obtaining reliable results in an affordable computer time.

[ES] El objetivo del presente Trabajo Final de Máster (TFM) es realizar un estudio dosimétrico de un tratamiento de braquiterapia hepática que emplea microesferas de Y-90 mediante simulación empleando el método de Monte Carlo. Si bien, un tratamiento de braquiterapia consiste en la introducción de la fuente en el interior del tumor, en concreto, para los carcinomas hepáticos, se emplea la radioembolización que consiste en la introducción de dichas semillas mediante la arteria hepática. Por ello, es importante conocer la dosis exacta que recibe el hígado, así como otros órganos colindantes que se pueden ver vascularmente afectados como es el caso del pulmón o el tracto gastrointestinal. Para ello, se emplea el modelo anatómico 3D distribuido recientemente por la Comisión Internacional de Protección Radiológica (ICRP) conocido como Fantoma Computacional de Referencia de Tipo de Malla (MRCP). Una vez segmentado el maniquí, se simula el tratamiento con el método de Monte Carlo, haciendo uso del código MCNP, introduciendo una fuente de Y-90 en el interior del hígado, así como todas las especificaciones de la física del transporte de fotones y electrones necesaria para la simulación. Como resultado, se obtiene la dosis que recibe el tumor del hígado, así como cada órgano colindante en un tratamiento de estas características. Se comprueba, además, que las dosis recibidas son seguras y se ajustan con los resultados empíricos. Con ello se demuestra que este método de simulación puede resultar adecuado para planificar tratamientos de braquiterapia obteniendo resultados fiables en un tiempo de computación asequible., [EN] The objective of this Master's Final Project (TFM) is to carry out a dosimetric study of a liver brachytherapy treatment that uses Y-90 microspheres by simulation using the Monte Carlo method. Although, a brachytherapy treatment consists of the introduction of the source into the tumor, in particular, for liver carcinomas, radioembolization is used, which consists of the introduction of these seeds through the hepatic artery. Therefore, it is important to know the exact dose received by the liver, as well as other adjoining organs that may be vascularly affected as is the case of the lung or the gastrointestinal tract. To do this, the 3D anatomical model recently distributed by the International Commission on Radiological Protection (ICRP) known as Mesh Type Reference Computational Fantoma (MRCP) is used. Once the mannequin is segmented, the treatment is simulated with the Monte Carlo method, making use of the MCNP code, introducing a Y-90 source inside the liver, as well as all the specifications of the physics of photon and electron transport necessary for the simulation. As a result, the dose received by the liver tumor is obtained, as well as each adjoining organ in a treatment of these characteristics. It is also verified that the doses received are safe and are adjusted with the empirical results. This demonstrates that this simulation method can be suitable for planning brachytherapy treatments obtaining reliable results in an affordable computer time.

[ES] El objetivo del presente Trabajo Final de Máster (TFM) es realizar un estudio dosimétrico de un tratamiento de braquiterapia hepática que emplea microesferas de Y-90 mediante simulación empleando el método de Monte Carlo. Si bien, un tratamiento de braquiterapia consiste en la introducción de la fuente en el interior del tumor, en concreto, para los carcinomas hepáticos, se emplea la radioembolización que consiste en la introducción de dichas semillas mediante la arteria hepática. Por ello, es importante conocer la dosis exacta que recibe el hígado, así como otros órganos colindantes que se pueden ver vascularmente afectados como es el caso del pulmón o el tracto gastrointestinal. Para ello, se emplea el modelo anatómico 3D distribuido recientemente por la Comisión Internacional de Protección Radiológica (ICRP) conocido como Fantoma Computacional de Referencia de Tipo de Malla (MRCP). Una vez segmentado el maniquí, se simula el tratamiento con el método de Monte Carlo, haciendo uso del código MCNP, introduciendo una fuente de Y-90 en el interior del hígado, así como todas las especificaciones de la física del transporte de fotones y electrones necesaria para la simulación. Como resultado, se obtiene la dosis que recibe el tumor del hígado, así como cada órgano colindante en un tratamiento de estas características. Se comprueba, además, que las dosis recibidas son seguras y se ajustan con los resultados empíricos. Con ello se demuestra que este método de simulación puede resultar adecuado para planificar tratamientos de braquiterapia obteniendo resultados fiables en un tiempo de computación asequible., [EN] The objective of this Master's Final Project (TFM) is to carry out a dosimetric study of a liver brachytherapy treatment that uses Y-90 microspheres by simulation using the Monte Carlo method. Although, a brachytherapy treatment consists of the introduction of the source into the tumor, in particular, for liver carcinomas, radioembolization is used, which consists of the introduction of these seeds through the hepatic artery. Therefore, it is important to know the exact dose received by the liver, as well as other adjoining organs that may be vascularly affected as is the case of the lung or the gastrointestinal tract. To do this, the 3D anatomical model recently distributed by the International Commission on Radiological Protection (ICRP) known as Mesh Type Reference Computational Fantoma (MRCP) is used. Once the mannequin is segmented, the treatment is simulated with the Monte Carlo method, making use of the MCNP code, introducing a Y-90 source inside the liver, as well as all the specifications of the physics of photon and electron transport necessary for the simulation. As a result, the dose received by the liver tumor is obtained, as well as each adjoining organ in a treatment of these characteristics. It is also verified that the doses received are safe and are adjusted with the empirical results. This demonstrates that this simulation method can be suitable for planning brachytherapy treatments obtaining reliable results in an affordable computer time.

[ES] El objetivo del presente Trabajo Final de Máster (TFM) es realizar un estudio dosimétrico de un tratamiento de braquiterapia hepática que emplea microesferas de Y-90 mediante simulación empleando el método de Monte Carlo. Si bien, un tratamiento de braquiterapia consiste en la introducción de la fuente en el interior del tumor, en concreto, para los carcinomas hepáticos, se emplea la radioembolización que consiste en la introducción de dichas semillas mediante la arteria hepática. Por ello, es importante conocer la dosis exacta que recibe el hígado, así como otros órganos colindantes que se pueden ver vascularmente afectados como es el caso del pulmón o el tracto gastrointestinal. Para ello, se emplea el modelo anatómico 3D distribuido recientemente por la Comisión Internacional de Protección Radiológica (ICRP) conocido como Fantoma Computacional de Referencia de Tipo de Malla (MRCP). Una vez segmentado el maniquí, se simula el tratamiento con el método de Monte Carlo, haciendo uso del código MCNP, introduciendo una fuente de Y-90 en el interior del hígado, así como todas las especificaciones de la física del transporte de fotones y electrones necesaria para la simulación. Como resultado, se obtiene la dosis que recibe el tumor del hígado, así como cada órgano colindante en un tratamiento de estas características. Se comprueba, además, que las dosis recibidas son seguras y se ajustan con los resultados empíricos. Con ello se demuestra que este método de simulación puede resultar adecuado para planificar tratamientos de braquiterapia obteniendo resultados fiables en un tiempo de computación asequible., [EN] The objective of this Master's Final Project (TFM) is to carry out a dosimetric study of a liver brachytherapy treatment that uses Y-90 microspheres by simulation using the Monte Carlo method. Although, a brachytherapy treatment consists of the introduction of the source into the tumor, in particular, for liver carcinomas, radioembolization is used, which consists of the introduction of these seeds through the hepatic artery. Therefore, it is important to know the exact dose received by the liver, as well as other adjoining organs that may be vascularly affected as is the case of the lung or the gastrointestinal tract. To do this, the 3D anatomical model recently distributed by the International Commission on Radiological Protection (ICRP) known as Mesh Type Reference Computational Fantoma (MRCP) is used. Once the mannequin is segmented, the treatment is simulated with the Monte Carlo method, making use of the MCNP code, introducing a Y-90 source inside the liver, as well as all the specifications of the physics of photon and electron transport necessary for the simulation. As a result, the dose received by the liver tumor is obtained, as well as each adjoining organ in a treatment of these characteristics. It is also verified that the doses received are safe and are adjusted with the empirical results. This demonstrates that this simulation method can be suitable for planning brachytherapy treatments obtaining reliable results in an affordable computer time.

AIM: The manufacturers' recommended methods to calculate delivered activities in liver radioembolization are simplistic and only slightly personalized. Activity planning could also be based on a 99mTc-macroaggregated albumin SPECT/CT (MAA) using the partition model but its accuracy is controversial. This study evaluates the dose parameters in the normal liver and in the tumor compartments using MAA SPECT/CT (pre-therapeutic imaging) and 90Y TOF-PET/CT (post-therapy imaging). Finally, we propose a prescription of the activity as a function of the normal liver MAA distribution. METHOD: 66 procedures of RE (with resin microspheres) corresponding to 171 lesions were analyzed. Tumor to normal targeted liver uptake (T/NTL), tumor absorbed dose (TD) and whole normal liver absorbed (WNLD) were assessed with MAA and 90Y imaging. Secondly, activities were recalculated using the MAA distribution in the normal liver compartment to reach the maximal tolerable liver dose. These Activities were compared to activities defined with the BSA method. RESULTS: Compared to 90Y imaging, our study demonstrated an accurate estimation of the WNLD using MAA imaging (Pearson's R = 0.97, p < 0.001). On the contrary, significant variations were found for TD (R = 0.65, p < 0.001). The MAA T/NTL ratio has a 85% positive predictive value in identifying patients who will get a 90Y T/NTL ratio above 1.5. Moreover, activities calculated using the MAA distribution in the normal liver compartment were significantly higher to activities defined with the BSA method. CONCLUSION: Whole normal liver absorbed doses are accurately predicted with MAA imaging and could be used to optimize the activity planning.

Explaining why Y TOF-PET based equivalent uniform dose (EUD) using recommended manufacturer FDG reconstruction parameters has been shown to predict response. The hot rods insert of a Jaszczak deluxe phantom was partially filled with a 2.65 GBq Y - 300ml DTPA water solution resulting in a 100 Gy mean absorbed dose in the 6 sectors. A two bed 20min/position acquisition was performed on a 550ps- and on a 320ps- TOF-PET/CT and reconstructed with recommended manufacturer FDG reconstruction parameters, without and with additional filtering. The whole procedure was repeated on both PET after adding 300ml of water (50Gy setup). The phantom was acquired again after decay by a factor of 10 (5Gy setup), but with 200min per bed position. For comparison, the phantom was also acquired with F activity corresponding to a clinical FDG whole body acquisition. The 100Gy-setup provided a hot rod sectors image almost as good as the F phantom. However, despite acquisition time compensation, the 5Gy-setup provides much lower quality imaging. TOF-PET based sectors EUDs for the three large rod sectors agreed with the actual EUDs computed with a radiosensitivity of 0.021Gy well in the range observed in external beam radiotherapy (EBRT), i.e. 0.01-0.04Gy. This agreement explains the reunification of the dose-response relationships of the glass and resin spheres in HCC using the TOF-PET based EUD. Additional filtering reduced the EUDs agreement quality. Recommended manufacturer FDG reconstruction parameters are suitable in TOF-PET post Y liver radioembolization for accurate tumour EUD computation. The present results rule out the use of low specific activity phantom studies to optimize reconstruction parameters.

Cholangiocarcinoma accounts for approximately 10% of all hepatobiliary tumors and represents 3% of all new-diagnosed malignancies worldwide. Intrahepatic cholangiocarcinoma (i-CCA) accounts for 10% of all cases, perihilar (h-CCA) cholangiocarcinoma represents two-thirds of the cases, while distal cholangiocarcinoma accounts for the remaining quarter. Originally described by Klatskin in 1965, h-CCA represents one of the most challenging tumors for hepatobiliary surgeons, mainly because of the anatomical vascular relationships of the biliary confluence at the hepatic hilum. Surgery is the only curative option, with the goal of a radical, margin-negative (R0) tumor resection. Continuous efforts have been made by hepatobiliary surgeons in order to achieve R0 resections, leading to the progressive development of aggressive approaches that include extended hepatectomies, associating liver partition, and portal vein ligation for staged hepatectomy, preoperative portal vein embolization, and vascular resections. i-CCA is an aggressive biliary cancer that arises from the biliary epithelium proximal to the second-degree bile ducts. The incidence of i-CCA is dramatically increasing worldwide, and surgical resection is the only potentially curative therapy. An aggressive surgical approach, including extended liver resection and vascular reconstruction, and a greater application of systemic therapy and locoregional treatments could lead to an increase in the resection rate and the overall survival in selected i-CCA patients. Improvements achieved over the last two decades and the encouraging results recently reported have led to liver transplantation now being considered an appropriate indication for CCA patients.

Purpose: The careful evaluation of MDCT is an essential step for the treatment planning in pre-treatment imaging work-up for Trans-Arterial Radio Embolization (TARE). It may provide unique volumetric data (CTVs), which are information useful for an effective and safe TARE. The purpose of this study is to demonstrate that the radiographer is able to calculate CTVs of TARE simulation with the same precision as the interventional radiologist. Methods: This study retrospectively considers 17 consecutive patients (8 males, 9 females; mean age 66.3 ± 13.2 years) who underwent pre-treatment work-up for TARE, between May 2019 and February 2020 (trial ID:2234 - protocol). For each patient, four specific parameters are evaluated from MDCT achieved during treatment simulation: healthy liver volume (HLV), the whole hepatic parenchyma (THV = healthy liver and TTV = tumour) involved by TARE, and whole liver volume (WLV). Four independent observers—R1 (expert interventional radiologist), T1, T2, and T3 (radiographers, with different experiences in the field of interventional radiology)—are involved in the imaging analysed. Results: All the 4 observers detected the same number of hepatic lesion(s) per patient. Regarding the three radiographers, the intra-observer reliability for CTVs is very high 0.997 to 1.000 (95%CI). Also inter-observer reproducibility between radiographers is excellent regarding CTVs, 0.965 to 0.999 (95%CI). The accuracy of radiographer evaluation is very high 0.964 to 0.999 (95%CI). Conclusions and implications for practice: The high intra- and inter-observer reproducibility shows that a properly trained radiographers might have the same accuracy as interventional radiologists, in assessing liver CTV data for planning TARE.

Background: Hepatocellular carcinoma (HCC) is responsible for 1% of deaths worldwide, and the incidence continues to increase. Despite surveillance programs, 70% of HCC patients are not suitable for curative options at diagnosis, and therefore, non-curative treatments are essential to modern clinical practice. There are many novel treatments, though their roles are not well defined. This study aimed to contrast Selective Internal Radiation Therapy (SIRT) and Drug Eluting Bead Transarterial Chemoembolisation (DEB-TACE) to further define their roles. Method(s): This was a retrospective multicentre cohort study. Factors included for analysis were type of HCC treatment, number of lesions, lesion size, multiple disease severity scores, cirrhosis and vascular invasion. The primary endpoint was transplant-free survival. Result(s): Transplant-free survival was similar between the two cohorts (p = 0.654), despite a variation in median lesion size, SIRT: 54.5 mm, DEB-TACE: 34 mm (p <= 0.001). A univariate Cox proportional hazard model utilising treatment modality as the covariate showed no significant difference in survival (DEB-TACE HR 1.4 (95%CI 0.85-2.15 p = 0.207). The size of the largest lesion was the best predictor of 3-year survival (p = 0.035). Lesion size was inversely associated with survival (HR 1.01 (95%CI 1-1.02, p = 0.025)) on multivariate analysis. Conclusion(s): This study is the first to catalogue the experience of using SIRT in HCC in a real-world Australian population. It has demonstrated no difference in survival outcomes between DEB-TACE and SIRT. Further, it has shown SIRT to be a reasonable alternative to DEB-TACE especially in larger lesions and has demonstrated that DEB-TACE has a role in select patients with advanced disease.Copyright © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Transarterial embolization is a minimally invasive treatment for advanced liver cancer using microspheres loaded with a chemotherapeutic drug or radioactive yttrium-90 (90Y) that are injected into the hepatic arterial tree through a catheter. For personalized treatment, the microsphere distribution in the liver should be optimized through the injection volume and location. Computational fluid dynamics (CFD) simulations of the blood flow in the hepatic artery can help estimate this distribution if carefully parameterized. An important aspect is the choice of the boundary conditions imposed at the inlet and outlets of the computational domain. In this study, the effect of boundary conditions on the hepatic arterial tree hemodynamics was investigated. The outlet boundary conditions were modeled with three-element Windkessel circuits, representative of the downstream vasculature resistance. Results demonstrated that the downstream vasculature resistance affected the hepatic artery hemodynamics such as the velocity field, the pressure field and the blood flow streamline trajectories. Moreover, the number of microspheres received by the tumor significantly changed (more than 10% of the total injected microspheres) with downstream resistance variations. These findings suggest that patient-specific boundary conditions should be used in order to achieve a more accurate drug distribution estimation with CFD in transarterial embolization treatment planning.

Background: Hepatocellular carcinoma (HCC) is responsible for 1% of deaths worldwide, and the incidence continues to increase. Despite surveillance programs, 70% of HCC patients are not suitable for curative options at diagnosis, and therefore, non-curative treatments are essential to modern clinical practice. There are many novel treatments, though their roles are not well defined. This study aimed to contrast Selective Internal Radiation Therapy (SIRT) and Drug Eluting Bead Transarterial Chemoembolisation (DEB-TACE) to further define their roles. Method(s): This was a retrospective multicentre cohort study. Factors included for analysis were type of HCC treatment, number of lesions, lesion size, multiple disease severity scores, cirrhosis and vascular invasion. The primary endpoint was transplant-free survival. Result(s): Transplant-free survival was similar between the two cohorts (p = 0.654), despite a variation in median lesion size, SIRT: 54.5 mm, DEB-TACE: 34 mm (p <= 0.001). A univariate Cox proportional hazard model utilising treatment modality as the covariate showed no significant difference in survival (DEB-TACE HR 1.4 (95%CI 0.85-2.15 p = 0.207). The size of the largest lesion was the best predictor of 3-year survival (p = 0.035). Lesion size was inversely associated with survival (HR 1.01 (95%CI 1-1.02, p = 0.025)) on multivariate analysis. Conclusion(s): This study is the first to catalogue the experience of using SIRT in HCC in a real-world Australian population. It has demonstrated no difference in survival outcomes between DEB-TACE and SIRT. Further, it has shown SIRT to be a reasonable alternative to DEB-TACE especially in larger lesions and has demonstrated that DEB-TACE has a role in select patients with advanced disease.Copyright © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Transarterial embolization is a minimally invasive treatment for advanced liver cancer using microspheres loaded with a chemotherapeutic drug or radioactive yttrium-90 (90Y) that are injected into the hepatic arterial tree through a catheter. For personalized treatment, the microsphere distribution in the liver should be optimized through the injection volume and location. Computational fluid dynamics (CFD) simulations of the blood flow in the hepatic artery can help estimate this distribution if carefully parameterized. An important aspect is the choice of the boundary conditions imposed at the inlet and outlets of the computational domain. In this study, the effect of boundary conditions on the hepatic arterial tree hemodynamics was investigated. The outlet boundary conditions were modeled with three-element Windkessel circuits, representative of the downstream vasculature resistance. Results demonstrated that the downstream vasculature resistance affected the hepatic artery hemodynamics such as the velocity field, the pressure field and the blood flow streamline trajectories. Moreover, the number of microspheres received by the tumor significantly changed (more than 10% of the total injected microspheres) with downstream resistance variations. These findings suggest that patient-specific boundary conditions should be used in order to achieve a more accurate drug distribution estimation with CFD in transarterial embolization treatment planning.

Yttrium-90 (Y-90) transarterial radioembolization uses radioactive microspheres injected into the hepatic artery to irradiate liver tumors internally. One of the major challenges is the lack of reliable dosimetry methods for dose prediction and dose verification. We present a patient-specific dosimetry approach for personalized treatment planning based on computational fluid dynamics (CFD) simulations of the microsphere transport combined with Y-90 physics modeling called CFDose. The ultimate goal is the development of a software to optimize the amount of activity and injection point for optimal tumor targeting. We present the proof-of-concept of a CFD dosimetry tool based on a patient's angiogram performed in standard-of-care planning. The hepatic arterial tree of the patient was segmented from the cone-beam CT (CBCT) to predict the microsphere transport using multiscale CFD modeling. To calculate the dose distribution, the predicted microsphere distribution was convolved with a Y-90 dose point kernel. Vessels as small as 0.45 mm were segmented, the microsphere distribution between the liver segments using flow analysis was predicted, the volumetric microsphere and resulting dose distribution in the liver volume were computed. The patient was imaged with positron emission tomography (PET) 2 h after radioembolization to evaluate the Y-90 distribution. The dose distribution was found to be consistent with the Y-90 PET images. These results demonstrate the feasibility of developing a complete framework for personalized Y-90 microsphere simulation and dosimetry using patient-specific input parameters.

PurposeTo evaluate the combination of 90Y radioembolization (Y90) and drug-eluting bead irinotecan (DEBIRI) microspheres in the VX2 rabbit model.Materials and methodsAn initial dose finding study was performed in 6 White New Zealand rabbits to identify a therapeutic but subcurative dose of Y90. In total, 29 rabbits were used in four groups: Y90 treatment (n = 8), DEBIRI treatment (n = 6), Y90 + DEBIRI treatment (n = 7), and an untreated control group (n = 8). Hepatic toxicity was evaluated at baseline, 24 h, 72 h, 1 week, and 2 weeks. MRI tumor volume (TV) and enhancing tumor volume were assessed baseline and 2 weeks. Tumor area and necrosis were evaluated on H&E for pathology.ResultsInfused activities of 84.0-94.4 MBq (corresponding to 55.1-72.7 Gy) were selected based on the initial dose finding study. Infusion of DEBIRI after Y90 was technically feasible in all cases (7/7). Overall, 21/29 animals survived to 2 weeks, and the remaining animals had extrahepatic disease on necropsy. Liver transaminases were elevated with Y90, DEBIRI, and Y90 + DEBIRI compared to control at 24 h, 72 h, and 1 week post-treatment and returned to baseline by 2 weeks. By TV, Y90 + DEBIRI was the only treatment to show statistically significant reduction at 2 weeks compared to the control group (p = 0.012). The change in tumor volume (week 2-baseline) for both Y90 + DEBIRI versus control (p = 0.002) and Y90 versus control (p = 0.014) was significantly decreased. There were no statistically significant differences among groups on pathology.ConclusionIntra-arterial Y90 + DEBIRI was safe and demonstrated enhanced antitumor activity in rabbit VX2 tumors. This combined approach warrants further investigation.

Interventional oncology represents a relatively new clinical discipline based upon minimally invasive therapies applicable to almost every human organ and disease. Over the last several decades, rapidly evolving research developments have introduced a newer generation of treatment devices, reagents, and image-guidance systems to expand the armamentarium of interventional oncology across a wide spectrum of disease sites, offering potential cure, control, or palliative care for many types of cancer patients. Due to the widespread use of locoregional procedures, a comprehensive review of the methodologic and technical considerations to optimize patient selection with the aim of performing a safe procedure is mandatory. This article summarizes the expert discussion and report from the Mediterranean Interventional Oncology Live Congress (MIOLive 2020) held in Rome, Italy, integrating evidence-reported literature and experience-based perceptions as a means for providing guidance on prudent ways to reduce complications. The aim of the paper is to provide an updated guiding tool not only to residents and fellows but also to colleagues approaching locoregional treatments.

Purpose: Reported outcomes of patients with intra-hepatic cholangiocarcinoma (IH-CCA) treated with radioembolization are highly variable, which indicates differences in included patients’ characteristics and/or procedure-related variables. This study aimed to identify patient- and treatment-related variables predictive for radioembolization outcome. Methods: This retrospective multicenter study enrolled 58 patients with unresectable and chemorefractory IH-CCA treated with resin 90Y-microspheres. Clinicopathologic data were collected from patient records. Metabolic parameters of liver tumor(s) and presence of lymph node metastasis were measured on baseline 18F-FDG-PET/CT. 99mTc-MAA tumor to liver uptake ratio (TLRMAA) was computed for each lesion on the SPECT-CT. Activity prescription using body-surface-area (BSA) or more personalized partition-model was recorded. The study endpoint was overall survival (OS) starting from date of radioembolization. Statistical analysis was performed by the log-rank test and multivariate Cox’s proportional hazards model. Results: Median OS (mOS) post-radioembolization of the entire cohort was 10.3 months. Variables associated with significant differences in terms of OS were serum albumin (hazard ratio (HR) = 2.78, 95%CI:1.29–5.98, p = 0.002), total bilirubin (HR = 2.17, 95%CI:1.14–4.12, p = 0.009), aspartate aminotransferase (HR = 2.96, 95%CI:1.50–5.84, p < 0.001), alanine aminotransferase (HR = 2.02, 95%CI:1.05–3.90, p = 0.01) and γ-GT (HR = 2.61, 95%CI:1.31–5.22, p < 0.001). The presence of lymph node metastasis as well as a TLRMAA < 1.9 were associated with shorter mOS: HR = 2.35, 95%CI:1.08–5.11, p = 0.008 and HR = 2.92, 95%CI:1.01–8.44, p = 0.009, respectively. Finally, mOS was significantly shorter in patients treated according to the BSA method compared to the partition-model: mOS of 5.5 vs 14.9 months (HR = 2.52, 95%CI:1.23–5.16, p < 0.001). Multivariate analysis indicated that the only variable that increased outcome predicti, SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose: Peptide receptor radionuclide therapy (PRRT) and radioembolization are increasingly used in neuroendocrine neoplasms patients. However, concerns have been raised on cumulative hepatotoxicity. The aim of this sub-analysis was to investigate hepatotoxicity of yttrium-90 resin microspheres radioembolization in patients who were previously treated with PRRT. Methods: Patients treated with radioembolization after systemic radionuclide treatment were retrospectively analysed. Imaging response according to response evaluation criteria in solid tumours (RECIST) v1.1 and clinical response after 3 months were collected. Clinical, biochemical and haematological toxicities according to common terminology criteria for adverse events (CTCAE) v4.03 were also collected. Specifics on prior PRRT, subsequent radioembolization treatments, treatments after radioembolization and overall survival (OS) were collected. Results: Forty-four patients were included, who underwent a total of 58 radioembolization procedures, of which 55% whole liver treatments, at a median of 353 days after prior PRRT. According to RECIST 1.1, an objective response rate of 16% and disease control rate of 91% were found after 3 months. Clinical response was seen in 65% (15/23) of symptomatic patients after 3 months. Within 3 months, clinical toxicities occurred in 26%. Biochemical and haematological toxicities CTCAE grade 3–4 occurred in ≤ 10%, apart from lymphocytopenia (42%). Radioembolization-related complications occurred in 5% and fatal radioembolization-induced liver disease in 2% (one patient). A median OS of 3.5 years [95% confidence interval 1.8–5.1 years] after radioembolization for the entire study population was found. Conclusion: Radioembolization after systemic radionuclide treatments is safe, and the occurrence of radioembolization-induced liver disease is rare. Level of Evidence: 4, case series., SCOPUS: ar.j, info:eu-repo/semantics/published

Hepatic radioembolization therapies can suffer from discrepancies between diagnostic planning (scout-scan) and the therapeutic delivery itself, resulting in unwanted side-effects such as pulmonary shunting. We reasoned that a nanotechnology-based pre-targeting strategy could help overcome this shortcoming by directly linking pre-interventional diagnostics to the local delivery of therapy. Methods: The host-guest interaction between adamantane and cyclodextrin was employed in an in vivo pre-targeting set-up. Adamantane (guest)-functionalized macro albumin aggregates (MAA-Ad; d = 18 μm) and (radiolabeled) Cy5 and β-cyclodextrin (host)-containing PIBMA polymers (99mTc-Cy50.5CD10PIBMA39; MW ~ 18.8 kDa) functioned as the reactive pair. Following liver or lung embolization with (99mTc)-MAA-Ad or (99mTc)-MAA (controls), the utility of the pre-targeting concept was evaluated after intravenous administration of 99mTc-Cy50.5CD10PIBMA39. Results: Interactions between MAA-Ad and Cy50.5CD10PIBMA39 could be monitored in solution using confocal microscopy and were quantified by radioisotope-based binding experiments. In vivo the accumulation of the MAA-Ad particles in the liver or lungs yielded an approximate ten-fold increase in accumulation of 99mTc-Cy50.5CD10PIBMA39 in those organs (16.2 %ID/g and 10.5 %ID/g, respectively) compared to the control. Pre-targeting with MAA alone was shown to be only half as efficient. Uniquely, for the first time, this data demonstrates that the formation of supramolecular interactions between cyclodextrin and adamantane can be used to drive complex formation in the chemically challenging in vivo environment. Conclusion: The in vivo distribution pattern of the cyclodextrin host could be guided by the pre-administration of the adamantane guest, thereby creating a direct link between the scout-scan (MAA-Ad) and delivery of therapy.

Background: Neuroendocrine tumours (NET) consist of a heterogeneous group of neoplasms with various organs of origin. At diagnosis 21% of the patients with a Grade 1 NET and 30% with a Grade 2 NET have distant metastases. Treatment with peptide receptor radionuclide therapy (PRRT) shows a high objective response rate and long median survival after treatment. However, complete remission is almost never achieved. The liver is the most commonly affected organ in metastatic disease and is the most incriminating factor for patient survival. Additional treatment of liver disease after PRRT may improve outcome in NET patients. Radioembolization is an established therapy for liver metastasis. To investigate this hypothesis, a phase 2 study was initiated to assess effectiveness and toxicity of holmium-166 radioembolization (166Ho-RE) after PRRT with lutetium-177 (177Lu)-DOTATATE. Methods: The HEPAR PLUS trial ("H olmium E mbolization P articles for A rterial R adiotherapy P lus 177 Lu -DOTATATE in S alvage NET patients") is a single centre, interventional, non-randomized, non-comparative, open label study. In this phase 2 study 30-48 patients with > 3 measurable liver metastases according to RECIST 1.1 will receive additional 166Ho-RE within 20 weeks after the 4th and last cycle of PRRT with 7.4 GBq 177Lu-DOTATATE. Primary objectives are to assess tumour response, complete and partial response according to RECIST 1.1, and toxicity, based on CTCAE v4.03, 3 months after 166Ho-RE. Secondary endpoints include biochemical response, quality of life, biodistribution and dosimetry. Discussion: This is the first prospective study to combine PRRT with 177Lu-DOTATATE and additional 166Ho-RE in metastatic NET. A radiation boost on intrahepatic disease using 166Ho-RE may lead to an improved response rate without significant additional side-effects.

Background and aims. A subclassification system for intermediate hepatocellular carcinoma (HCC) was recently proposed to optimize treatment allocation. The aim of this study was to assess the prognostic ability of that substaging proposal. Patients and methods. This is a retrospective multicenter cohort study including patients with intermediate HCC treated with transarterial chemoembolization (TACE). Predictors of survival were identified using the Cox proportional regression model. Results. 289 Barcelona Clinic Liver Cancer (BCLC) B patients were included. Median overall survival of the whole cohort was 23 months (C.I. 95% 20.2-25.8). Child A status (H.R. 1.35, C.I. 95% 1.02-1.78) and tumour burden beyond the up-to-seven criterion (H.R. 1.39, C.I. 95% 1.07-1.80) were independent prognostic factors for overall survival on multivariate analysis. Analysis of the substages showed that median survival was 33.0 months for B1 stage (n = 81), 20.8 months for B2 stage (n = 106), 16.1 months for B3 stage (n = 24), 22.2 months for B4 stage (n = 42) and 15.0 months for quasi-C stage (n = 36). Regarding the discriminatory ability of the substaging proposal, the log rank test showed a significant survival difference for B1vs. B4 (p = 0.003) and B1 vs. Quasi-C (p = 0.039) and a trend for B1 vs. B2 (p = 0.05) and B1 vs. B3 (p = 0.05). Conclusions. Apart from substage B1, BCLC-B subclassification does not discriminate perfectly patients treated with TACE. Also some patients in substage B4 can benefit from TACE.

Radioembolization of liver tumors using yttrium-90 (Y-90) labeled microspheres is a proven method of treatment. The primary decay mode of Y-90 is beta-minus decay. The electrons produced during decay deliver a cytotoxic radiation dose in a localized volume. The radiation dose is sufficient to kill tumor cells yet spare the normal liver. The Y-90 microspheres are delivered via a catheter that has been placed in an artery that supplies blood to the tumor. Microspheres are injected and the blood distributes the microspheres. The current practice involves two separate procedures. The first procedure is an assessment of the vasculature of the liver and tumor. This assessment is performed with radiolabeled macro-aggregated albumin particles (Tc-99m MAA). The Tc-99m MAA is injected via a catheter placed in the same location that will be used for the delivery of Y-90 microspheres. The distribution of the Tc-99m MAA particles is imaged using a gamma camera. This data is used to predict the microsphere distribution and subsequent dose to the tumor, normal liver, lungs and other organs. The data may be used to adjust the Y-90 activity and to perform crude pre-treatment dosimetry. Accurate pre-treatment dosimetry is largely absent. This study was performed to create a positron-emitting surrogate microsphere that was close in size and shape to the Y-90 microspheres. Positron emission tomography (PET) is superior to SPECT for activity quantification. Fluorine-18 (F-18) was chosen for initial experiments. There were two aims of the research: Aim 1: To develop surrogate PET microsphere. This included radiolabeling, stability testing in vitro and stability testing in an animal. Aim 2: To develop a computational technique to perform dosimetry with the surrogate microsphere. PET images of the surrogate radionuclide were imported into a Monte Carlo program. PET images were used to simulate the distribution of the Y-90 microspheres. The output of the simulation w

Management of hepatocellular carcinoma (HCC) can be maximized with the utilization of multiple treatment modalities including transplant, surgical resection and locoregional therapies including ablative therapies and transarterial embolotherapies. Although transplant and surgical resection offer the best clinical outcomes, a limited number of patients are amenable to these surgical treatment options due to the advanced disease at presentation. Transarterial embolotherapies including conventional transarterial chemoembolization (cTACE), bland transarterial embolization (TAE), drug-eluting beads transarterial chemoembolization (DEB-TACE) and selective internal radiation therapy (SIRT) with Yttrium 90 (90Y) have played an increasingly important role for these patients with unresectable HCC. With a better understanding of different transarterial embolotherapies, more personalized and precise treatment should be implemented for these patients with unresectable HCC. In this review, the updated evidence on the current role of each embolotherapy in the treatment of HCC is summarized.

Purpose: To establish the relationship between common mutations in the MAPK and PI3K signaling pathways and local progression after radioembolization. Materials and methods: Retrospective review of a HIPAA-compliant institutional review-board approved database identified 40 patients with chemo-refractory colorectal liver metastases treated with radioembolization who underwent tumor genotyping for hotspot mutations in 6 key genes in the MAPK/PI3K pathways (KRAS, NRAS, BRAF, MEK1, PIK3CA, and AKT1). Mutation status as well as clinical, tumor, and treatment variables were recorded. These factors were evaluated in relation to time to local progression (TTLP), which was calculated from time of radioembolization to first radiographic evidence of local progression. Predictors of outcome were identified using a proportional hazards model for both univariate and multivariate analysis with death as a competing risk. Results: Sixteen patients (40%) had no mutations in either pathway, eighteen patients (45%) had mutations in the MAPK pathway, ten patients (25%) had mutations in the PI3K pathway and four patients (10%) had mutations in both pathways. The cumulative incidence of progression at 6 and 12 months was 33% and 55% for the PI3K mutated group compared with 76% and 92% in the PI3K wild type group. Mutation in the PI3K pathway was a significant predictor of longer TTLP in both univariate (p=0.031, sHR 0.31, 95% CI: 0.11-0.90) and multivariate (p=0.015, sHR=0.27, 95% CI: 0.096-0.77) analysis. MAPK pathway alterations were not associated with TTLP. Conclusions: PI3K pathway mutation predicts longer time to local progression after radioembolization of colorectal liver metastases.

Management of hepatocellular carcinoma (HCC) can be maximized with the utilization of multiple treatment modalities including transplant, surgical resection and locoregional therapies including ablative therapies and transarterial embolotherapies. Although transplant and surgical resection offer the best clinical outcomes, a limited number of patients are amenable to these surgical treatment options due to the advanced disease at presentation. Transarterial embolotherapies including conventional transarterial chemoembolization (cTACE), bland transarterial embolization (TAE), drug-eluting beads transarterial chemoembolization (DEB-TACE) and selective internal radiation therapy (SIRT) with Yttrium 90 (90Y) have played an increasingly important role for these patients with unresectable HCC. With a better understanding of different transarterial embolotherapies, more personalized and precise treatment should be implemented for these patients with unresectable HCC. In this review, the updated evidence on the current role of each embolotherapy in the treatment of HCC is summarized.

Metastatic colorectal cancer represents the most common liver malignancy, and imparts a very poor prognosis for those who develop this disease. Unlike primary liver tumors such as hepatocellular carcinoma, which largely develops in patients with underlying cirrhosis, most metastatic liver tumor patients have normal underlying liver function. Owing to this, most will succumb to tumoral replacement of the liver rather than from underlying liver dysfunction. Radioembolization represents a treatment modality that can be used in multiple fashions to treat one or both lobes of the liver. Techniques depend on whether the procedure is used as first-line, second/third-line, or as salvage therapy. Outcomes and complications of radioembolization are presented in this article, as well as background information on colorectal cancer and systemic therapies.

Purpose: To establish the relationship between common mutations in the MAPK and PI3K signaling pathways and local progression after radioembolization. Materials and methods: Retrospective review of a HIPAA-compliant institutional review-board approved database identified 40 patients with chemo-refractory colorectal liver metastases treated with radioembolization who underwent tumor genotyping for hotspot mutations in 6 key genes in the MAPK/PI3K pathways (KRAS, NRAS, BRAF, MEK1, PIK3CA, and AKT1). Mutation status as well as clinical, tumor, and treatment variables were recorded. These factors were evaluated in relation to time to local progression (TTLP), which was calculated from time of radioembolization to first radiographic evidence of local progression. Predictors of outcome were identified using a proportional hazards model for both univariate and multivariate analysis with death as a competing risk. Results: Sixteen patients (40%) had no mutations in either pathway, eighteen patients (45%) had mutations in the MAPK pathway, ten patients (25%) had mutations in the PI3K pathway and four patients (10%) had mutations in both pathways. The cumulative incidence of progression at 6 and 12 months was 33% and 55% for the PI3K mutated group compared with 76% and 92% in the PI3K wild type group. Mutation in the PI3K pathway was a significant predictor of longer TTLP in both univariate (p=0.031, sHR 0.31, 95% CI: 0.11-0.90) and multivariate (p=0.015, sHR=0.27, 95% CI: 0.096-0.77) analysis. MAPK pathway alterations were not associated with TTLP. Conclusions: PI3K pathway mutation predicts longer time to local progression after radioembolization of colorectal liver metastases.

Hepatocellular carcinoma is a primary liver cancer.Among treatment options for hepatocellular carcinoma, Yttrium-90 radioembolization is a promising transarterial therapy.This thesis investigates potential clinical applications of radioembolization in the treatment of the hepatocellular carcinoma (techniques of radiation segmentectomy and radiation lobectomy), and adress the problematic of the response Assessment after radioembolization., Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished

Preoperative radioembolization may improve the resectability of liver tumor by inducing tumor shrinkage, atrophy of the embolized liver and compensatory hypertrophy of non-embolized liver. We describe the case of a cirrhotic Child-Pugh A patient with a segment IV hepatocellular carcinoma requiring a left hepatectomy. Preoperative angiography demonstrated 2 separated left hepatic arteries, for segment IV and segments II-III. This anatomic variant allowed sequential radioembolizations, delivering high-dose 90Yttrium (160 Gy) to the tumor, followed 28 d later by lower dose (120 Gy) to segments II-III. After 3 mo, significant tumor response and atrophy of the future resected liver were obtained, allowing uneventful left hepatectomy. This case illustrates that, when anatomic disposition permits it, sequential radioembolizations, delivering different 90Yttrium doses to the tumor and the future resected liver, could represent a new strategy to prepare major hepatectomy in cirrhotic patients, allowing optimal tumoricidal effect while reducing the toxicity of the global procedure., SCOPUS: ar.j, info:eu-repo/semantics/published

Hepatocellular carcinoma is the most common primary liver cancer and it represents the majority of cancer-related deaths in the world. More than 70% of patients present at an advanced stage, beyond potentially curative options. Ytrrium-90 selective internal radiation therapy (Y90-SIRT) with glass microspheres is rapidly gaining acceptance as a potential therapy for intermediate and advanced stage primary hepatocellular carcinoma and liver metastases. The technique involves delivery of Y90 infused glass microspheres via the hepatic arterial blood flow to the appropriate tumor. The liver tumor receives a highly concentrated radiation dose while sparing the healthy liver parenchyma due to its preferential blood supply from portal venous blood. There are two commercially available devices: TheraSphere® and SIR-Spheres®. Although, Y90-SIRT with glass microspheres improves median survival in patients with intermediate and advanced hepatocellular carcinoma and has the potential to downstage hepatocellular carcinoma so that the selected candidates meet the transplantable criteria, it has not gained widespread acceptance due to the lack of large randomized controlled trials. Currently, there are various clinical trials investigating the use of Y90-SIRT with glass microspheres for treatment of hepatocellular carcinoma and the outcomes of these trials may result in the incorporation of Y90-SIRT with glass microspheres into the treatment guidelines as a standard therapy option for patients with intermediate and advanced stage hepatocellular carcinoma.

PurposeThe purpose of our study is to determine if there is a relationship between dose deposition measured by PET/MRI and individual lesion response to yttrium-90 ((90)Y) microsphere radioembolization.Materials and methods26 patients undergoing lobar treatment with (90)Y microspheres underwent PET/MRI within 66 h of treatment and had follow-up imaging available. Adequate visualization of tumor was available in 24 patients, and contours were drawn on simultaneously acquired PET/MRI data. Dose volume histograms (DVHs) were extracted from dose maps, which were generated using a voxelized dose kernel. Similar contours to capture dimensional and volumetric change of tumors were drawn on follow-up imaging. Response was analyzed using both RECIST and volumetric RECIST (vRECIST) criteria.ResultsA total of 8 hepatocellular carcinoma (HCC), 4 neuroendocrine tumor (NET), 9 colorectal metastases (CRC) patients, and 3 patients with other metastatic disease met inclusion criteria. Average dose was useful in predicting response between responders and non-responders for all lesion types and for CRC lesions alone using both response criteria (p < 0.05). D70 (minimum dose to 70 % of volume) was also useful in predicting response when using vRECIST. No significant trend was seen in the other tumor types. For CRC lesions, an average dose of 29.8 Gy offered 76.9 % sensitivity and 75.9 % specificity for response.ConclusionsPET/MRI of (90)Y microsphere distribution showed significantly higher DVH values for responders than non-responders in patients with CRC. DVH analysis of (90)Y microsphere distribution following treatment may be an important predictor of response and could be used to guide future adaptive therapy trials.

PurposeThe purpose of our study is to determine if there is a relationship between dose deposition measured by PET/MRI and individual lesion response to yttrium-90 ((90)Y) microsphere radioembolization.Materials and methods26 patients undergoing lobar treatment with (90)Y microspheres underwent PET/MRI within 66 h of treatment and had follow-up imaging available. Adequate visualization of tumor was available in 24 patients, and contours were drawn on simultaneously acquired PET/MRI data. Dose volume histograms (DVHs) were extracted from dose maps, which were generated using a voxelized dose kernel. Similar contours to capture dimensional and volumetric change of tumors were drawn on follow-up imaging. Response was analyzed using both RECIST and volumetric RECIST (vRECIST) criteria.ResultsA total of 8 hepatocellular carcinoma (HCC), 4 neuroendocrine tumor (NET), 9 colorectal metastases (CRC) patients, and 3 patients with other metastatic disease met inclusion criteria. Average dose was useful in predicting response between responders and non-responders for all lesion types and for CRC lesions alone using both response criteria (p < 0.05). D70 (minimum dose to 70 % of volume) was also useful in predicting response when using vRECIST. No significant trend was seen in the other tumor types. For CRC lesions, an average dose of 29.8 Gy offered 76.9 % sensitivity and 75.9 % specificity for response.ConclusionsPET/MRI of (90)Y microsphere distribution showed significantly higher DVH values for responders than non-responders in patients with CRC. DVH analysis of (90)Y microsphere distribution following treatment may be an important predictor of response and could be used to guide future adaptive therapy trials.

Hepatocellular carcinoma is the most common primary liver cancer and it represents the majority of cancer-related deaths in the world. More than 70% of patients present at an advanced stage, beyond potentially curative options. Ytrrium-90 selective internal radiation therapy (Y90-SIRT) with glass microspheres is rapidly gaining acceptance as a potential therapy for intermediate and advanced stage primary hepatocellular carcinoma and liver metastases. The technique involves delivery of Y90 infused glass microspheres via the hepatic arterial blood flow to the appropriate tumor. The liver tumor receives a highly concentrated radiation dose while sparing the healthy liver parenchyma due to its preferential blood supply from portal venous blood. There are two commercially available devices: TheraSphere® and SIR-Spheres®. Although, Y90-SIRT with glass microspheres improves median survival in patients with intermediate and advanced hepatocellular carcinoma and has the potential to downstage hepatocellular carcinoma so that the selected candidates meet the transplantable criteria, it has not gained widespread acceptance due to the lack of large randomized controlled trials. Currently, there are various clinical trials investigating the use of Y90-SIRT with glass microspheres for treatment of hepatocellular carcinoma and the outcomes of these trials may result in the incorporation of Y90-SIRT with glass microspheres into the treatment guidelines as a standard therapy option for patients with intermediate and advanced stage hepatocellular carcinoma.

PurposeThe purpose of our study is to determine if there is a relationship between dose deposition measured by PET/MRI and individual lesion response to yttrium-90 ((90)Y) microsphere radioembolization.Materials and methods26 patients undergoing lobar treatment with (90)Y microspheres underwent PET/MRI within 66 h of treatment and had follow-up imaging available. Adequate visualization of tumor was available in 24 patients, and contours were drawn on simultaneously acquired PET/MRI data. Dose volume histograms (DVHs) were extracted from dose maps, which were generated using a voxelized dose kernel. Similar contours to capture dimensional and volumetric change of tumors were drawn on follow-up imaging. Response was analyzed using both RECIST and volumetric RECIST (vRECIST) criteria.ResultsA total of 8 hepatocellular carcinoma (HCC), 4 neuroendocrine tumor (NET), 9 colorectal metastases (CRC) patients, and 3 patients with other metastatic disease met inclusion criteria. Average dose was useful in predicting response between responders and non-responders for all lesion types and for CRC lesions alone using both response criteria (p < 0.05). D70 (minimum dose to 70 % of volume) was also useful in predicting response when using vRECIST. No significant trend was seen in the other tumor types. For CRC lesions, an average dose of 29.8 Gy offered 76.9 % sensitivity and 75.9 % specificity for response.ConclusionsPET/MRI of (90)Y microsphere distribution showed significantly higher DVH values for responders than non-responders in patients with CRC. DVH analysis of (90)Y microsphere distribution following treatment may be an important predictor of response and could be used to guide future adaptive therapy trials.

BACKGROUND: This prospective pilot single-institution study was undertaken to document the feasibility, safety, and efficacy of radioembolization of liver-dominant metastatic gastrointestinal cancer using 90Y glass microspheres. METHODS: Between June 2010 and October 2013, 42 adult patients (26 men, 16 women; median age 60 years) with metastatic chemotherapy-refractory unresectable colorectal (n=21), neuroendocrine (n=11), intrahepatic bile duct (n=7), pancreas (n=2), and esophageal (n=1) carcinomas underwent 60 lobar or segmental administrations of 90Y glass microspheres. Data regarding clinical and laboratory adverse events (AE) were collected prospectively for up to 5.5 years after radioembolization. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Time to maximum response, response duration, progression-free survival (PFS) (hepatic and extrahepatic), and overall survival (OS) were measured. RESULTS: Median target dose and activity were 109.4 Gy and 2.6 GBq per treatment session, respectively. Majority of clinical AE were grade 1 or 2 in severity. Patients with colorectal cancer had hepatic objective response rate (ORR) of 25% and a hepatic disease control rate (DCR) of 80%. Median PFS and OS were 1.0 and 4.4 months, respectively. Patients with neuroendocrine tumors (NET) had hepatic ORR and DCR of 73% and 100%, respectively. Median PFS was 8.9 months for this cohort. DCR and median PFS and OS for patients with cholangiocarcinoma were 86%, 1.1 months, and 6.7 months, respectively. CONCLUSIONS: 90Y glass microspheres device has a favorable safety profile, and achieved prolonged disease control of hepatic tumor burden in a subset of patients, including all patients enrolled in the neuroendocrine cohort.

An obese 55-year-old woman with nonalcoholic fatty liver disease presented 7 years after resection of a T3N1 ileal carcinoid tumor with an elevated chromogranin A, multifocal metastatic disease to the liver, and carcinoid syndrome. She underwent right hepatic artery yttrium-90 (Y90) radioembolization, followed a month later by selective Y90 treatment to segment IV. She then presented to our clinic 10 months later, remaining symptomatic with flushing, diarrhea, anxiety, myalgia, pain, and persistent night sweats despite Sandostatin administration. At least 11 tumors were identified in the right lobe of the liver and three in segment IV on liver-specific imaging. These lesions were stable over a year with no new lesions. At exploration, there was marked hypertrophy of the left lateral segment due to the yttrium-90 treatment of segments IV-VIII, corresponding with preoperative volumetrics predicting a functional liver remnant (FLR) of 40% after extended right hepatectomy. The right lobe and segment IV were fibrotic, hard, and visibly damaged. The gland had a thick, fibrotic capsule, and the parenchyma was dense, inflexible, and difficult to dissect, consistent with the previously reported morbidity of these operations. Extended right hepatectomy was performed. Final pathology demonstrated 15 foci of metastatic well-differentiated neuroendocrine carcinoma that were negative for necrosis, as was expected given her continued symptoms despite radioembolization. Numerous amorphous spheres, frequently in clusters, were present in segments IV-VIII in vessels and approximating tumors consistent with prior Y90 radioembolization. The patient had an uneventful post-operative recovery and remains symptom free on follow-up. Treatment options for metastatic tumors to the liver have increased in recent years and currently include radioembolization in selected patients. Surgical cytoreduction and complete metastasectomy continue to offer improvement in symptoms, quality of life, and s

90Y-radioembolization is a palliative treatment for liver cancer. 90Y decays via beta emission, making imaging difficult due to absence of gamma radiation. Since post-procedure imaging is crucial, several theranostic radionuclides have been explored as alternatives. However, exposures to gamma radiation throughout the treatment caused concern for the organs near the liver. Geant4 Monte Carlo simulation using MIRD Pamphlet 5 reference phantom was carried out. A spherical tumour with 4.3cm radius was modelled within the liver. 1.82GBq of 90Y sources were isotropically distributed within the tumour, with no extrahepatic shunting. The simulation was repeated with 153Sm, 166Ho and 177Lu. The estimated tumour doses for all radionuclides were 262.9Gy. Tumour dose equivalent to 1.82GBq 90Y can be achieved with 8.32, 5.83, and 4.44GBq for 153Sm, 166Ho and 177Lu, respectively. Normal liver doses by the other radionuclides were lower than 90Y, hence beneficial for normal tissue sparing. The organ doses from 153Sm and 177Lu were relatively higher due to higher gamma energy, but were still well below 1Gy. 166Ho, 177Lu and 153Sm offer useful gamma emission for post-procedure imaging. They show potential as 90Y substitutes, delivering comparable tumour doses, lower normal liver doses and other organs doses far below the tolerance limit.

Purpose: To compare various computed tomography (CT) parameters to the positron emission tomography with computed tomography (PET-CT) response, with or without PET guidance for the response assessment of colorectal cancer (CRC) metastases treated by Y90 radioembolization. Methods: Thirty-six CRC metastases were retrospectively evaluated on 18F-Fluoro-Deoxy-Glucose PET-CT and contrast-enhanced computed tomography (CECT) performed at baseline and 2-3 months after Y90 radioembolization. Results: Median SUVmax values decreased from 11.39 to 6.71 after radioembolization (P< .001), and 23/36 (64%) metastases were categorized metabolic responses according to European Organisation for Research and Treatment of Cancer criteria. Only a decrease of the mean attenuation in the structural (P< .001) and metabolic active volume (P< .001) was observed. The change in these criteria was correlated with the change of SUVmax., SCOPUS: ar.j, info:eu-repo/semantics/published

The liver is a common site of metastasis, with essentially all metastatic malignancies having been known to spread to the liver. Nearly half of all patients with extrahepatic primary cancer have hepatic metastases. The severe prognostic implications of hepatic metastases have made surgical resection an important first line treatment in management. However, limitations such as the presence of extrahepatic spread or poor functional hepatic reserve exclude the majority of patients as surgical candidates, leaving chemotherapy and locoregional therapies as next best options. Selective internal radiation therapy (SIRT) is a form of catheter-based locoregional cancer treatment modality for unresectable tumors, involving trans-arterial injection of microspheres embedded with a radio-isotope Yttrium-90. The therapeutic radiation dose is selectively delivered as the microspheres permanently embed themselves within the tumor vascular bed. Use of SIRT has been conventionally aimed at treating primary hepatic tumors (hepatocellular carcinoma) or colorectal and neuroendocrine metastases. Numerous reviews are available for these tumor types. However, little is known or reviewed on non-colorectal or non-neuroendocrine primaries. Therefore, the aim of this paper is to systematically review the current literature to evaluate the effects of Yttrium-90 radioembolization on non-conventional liver tumors including those secondary to breast cancer, cholangiocarcinoma, ocular and percutaneous melanoma, pancreatic cancer, renal cell carcinoma, and lung cancer.

Purpose: To compare various computed tomography (CT) parameters to the positron emission tomography with computed tomography (PET-CT) response, with or without PET guidance for the response assessment of colorectal cancer (CRC) metastases treated by Y90 radioembolization. Methods: Thirty-six CRC metastases were retrospectively evaluated on 18F-Fluoro-Deoxy-Glucose PET-CT and contrast-enhanced computed tomography (CECT) performed at baseline and 2-3 months after Y90 radioembolization. Results: Median SUVmax values decreased from 11.39 to 6.71 after radioembolization (P< .001), and 23/36 (64%) metastases were categorized metabolic responses according to European Organisation for Research and Treatment of Cancer criteria. Only a decrease of the mean attenuation in the structural (P< .001) and metabolic active volume (P< .001) was observed. The change in these criteria was correlated with the change of SUVmax., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose: To investigate and compare the quantitative accuracy of 90Y imaging across different generation PET/CT scanners, for the purpose of dosimetry after radioembolization with resin microspheres. Methods: A strict experimental and imaging protocol was followed by 47 international sites using the NEMA 2007/IEC 2008 PET body phantom with an 8-to-1 sphere-to-background ratio of 90Y solution. The phantom was imaged over a 7-day period (activity ranging from 0.5 to 3.0 GBq) and all reconstructed data were analysed at a core laboratory for consistent processing. Quantitative accuracy was assessed through measures of total phantom activity, activity concentration in background and hot spheres, misplaced counts in a nonradioactive insert, and background variability. Results: Of the 69 scanners assessed, 37 had both time-of-flight (ToF) and resolution recovery (RR) capability. These current generation scanners from GE, Philips and Siemens could reconstruct background concentration measures to within 10 % of true values over the evaluated range, with greater deviations on the Philips systems at low count rates, and demonstrated typical partial volume effects on hot sphere recovery, which dominated spheres of diameter <20 mm. For spheres >20 mm in diameter, activity concentrations were consistently underestimated by about 20 %. Non-ToF scanners from GE Healthcare and Siemens were capable of producing accurate measures, but with inferior quantitative recovery compared with ToF systems. Conclusion: Current generation ToF scanners can consistently reconstruct 90Y activity concentrations, but they underestimate activity concentrations in small structures (≤37 mm diameter) within a warm background due to partial volume effects and constraints of the reconstruction algorithm. At the highest count rates investigated, measures of background concentration (about 300 kBq/ml) could be estimated on average to within 1 %, 5 % and 2 % for GE Healthcare (, 0, SCOPUS: ar.j, info:eu-repo/semantics/published

L’hypothèse prédominante de cette thèse est que les changements métaboliques tumoraux mesurés par FDG-PET/CT sous l’influence des traitements anticancéreux, apparaissent plus précocement et parfois exclusivement par rapport aux modalités d’imagerie morphologique classique. L’imagerie multimodale, en combinant les avantages de chacune des techniques, dépasse leur limitations et pourrait permettre (i) une évaluation du bénéfice du traitement plus rapide et plus adéquate ;(ii) de modifier les algorithmes thérapeutiques à différents stades de cancer colorectal et (iii) d’améliorer la compréhension des mécanismes d’échappement aux traitements anticancéreux. Pour évaluer l’apport de l’imagerie multimodale dans l’évaluation de la réponse au traitement des cancers colorectaux (CCR), nous avons poursuivi 3 séries d’expérimentation cliniques.1) Le premier projet explore l’imagerie multimodale comme un outil d’individualisation pour la radio-embolisation (microsphères chargées en 90Yttrium) chez des patients porteurs d’un CCR métastatique au niveau du foie, pour laquelle l’imagerie morphologique classique est incapable de mesurer l’effet thérapeutique. Nous montrons que l’usage non sélectif de la radio-embolisation améliore l’histoire clinique de ces patients, bien que certains d’entre eux ne semblent pas en bénéficier. Ensuite, par une analyse multimodale lésion par lésion intégrant angiographie-CT Scan, FDG-PET/CT et scintigraphie aux macro-agrégats d’albumine marqués au 99mTechnetium, nous démontrons que la distribution pré-thérapeutique des macro-agrégats d’albumine est hétérogène entre les différentes lésions des patients et prédictive de la réponse métabolique au sein de ces lésions, permettant le développement d’un outil de prédiction et de planification pour la radio-embolisation.2) Le deuxième projet explore le domaine du CCR métastatique traité par chimiothérapie palliative. (i) Nous démontrons d’abord que la réponse métabolique (RM) tumorale après une cu, Doctorat en Sciences médicales, info:eu-repo/semantics/nonPublished