Les microsphères d'embolisation, apparues dans les années 2000, sont des dispositifs médicaux dirigées contre les tumeurs hépatiques non opérables. Elles sont calibrés et peuvent être chargées en anticancéreux. Ces avancées majeures permettent de contrôler le niveau d'occlusion et la concentration en principe actif à injecter dans la tumeur. Cependant, le type, la taille des microsphères ou encore la concentration en anticancéreux varient d'un centre à un autre et d'un pays à un autre. Notre travail vise à comparer, sur des modèles de tumeurs hépatiques, les propriétés d'élution et l'efficacité antitumorale de différentes préparations de microsphères. La microspectroscopie infrarouge est utilisée pour mesurer la quantité de doxorubicine présente dans les microsphères à différents délais alors que la microspectrofluorimétrie permet d'évaluer la concentration et la distribution de la doxorubicine autour des billes. L'évaluation de l'activité antitumorale du traitement est mesurée sur les images spectrales infrarouge grâce à un modèle de prédiction et confirmée par un examen histopathologique. Les résultats ont montré que la vitesse d'élution dépend des propriétés physicochimiques de la microsphère, de sa taille et de la concentration de chargement. Les concentrations tissulaires de doxorubicine mesurées induisent une réduction significative de la viabilité tumorale. Le model de prédiction est un outil robuste et précis pour évaluer les modifications tissulaires. Ces résultats permettent de formuler des hypothèses mécanistiques sur l'activité antitumorale de différentes préparations de microsphères afin d'optimiser leur utilisation dans une stratégie thérapeutique clinique. / Transarterial chemoembolization is the most common treatment for patients with unresectable liver tumors. Calibrated drug eluting beads offer the advantages of controlling the level of occlusion, the amount of drug delivered, and the duration of drug delivery to the tumor. However, optimal procedure still remains unanswered and treatments differ through the use of various beads sizes or dose of loading. Our work is to compare, on experimental liver tumor model, the release properties and antitumor effects for different preparations of doxorubicin eluting beads. The amount of drug retained inside the beads, at different time point, is assessed by infrared microspectroscopy. Doxorubicin concentration and distribution in the tissue are determined by microspectrofluorimetry. Tissue modifications are quantified by a prediction model on infrared images and compared with the conventional pathological examination of stained tissue sections. Results show that elution rate of doxorubicin depend on the beads composition, the size and the loaded concentration. The doxorubicin tissue concentration induces a significant decrease of tumor viability. The prediction model established by infrared microspectroscopy is an accurate and robust tool to quantify tissue modifications. These results allow the formulation of mechanistic hypotheses on antitumor activity of different preparations of beads to optimize their use in a clinical therapeutic strategy.

Purpose: To evaluate the efficiency of a multimodality approach consisting of transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) as bridging therapy for patients with hepatocellular carcinoma (HCC) awaiting orthotopic liver transplantation (OLT) and to evaluate the histopathological response in explant specimens. Materials and Methods: Between April 2001 and November 2011, 36 patients with 50 HCC nodules (1.4–5.0 cm, median 2.8 cm) on the waiting list for liver transplantation were treated by TACE and RFA. The drop-out rate during the follow-up period was recorded. The local efficacy was evaluated by histopathological examination of the explanted livers. Results: During a median follow-up time of 29 (4.0–95.3) months the cumulative drop-out rate for the patients on the waiting list was 0, 2.8, 5.5, 11.0, 13.9 and 16.7% at 3, 6, 12, 24, 36 and 48 months, respectively. 16 patients (with 26 HCC lesions) out of 36 (44.4%) were transplanted by the end of study with a median waiting list time of 13.7 (2.5–37.8) months. The histopathological examination of the explanted specimens revealed a complete necrosis in 20 of 26 HCCs (76.9%), whereas 6 (23.1%) nodules showed viable residual tumor tissue. All transplanted patients are alive at a median time of 29.9 months. Imaging correlation showed 100% specificity and 66.7% sensitivity for the depiction of residual or recurrent tumor. Conclusion: We conclude that TACE combined with RFA could provide an effective treatment to decrease the drop-out rate from the OLT waiting list for HCC patients. Furthermore, this combination therapy results in high rates of complete tumor necrosis as evaluated in the histopathological analysis of the explanted livers. Further randomized trials are needed to demonstrate if there is a benefit in comparison with a single-treatment approach. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background and Aims: Morphometric features such as the Milan criteria serve as standard criteria for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Since it has been recognized that these criteria are too restrictive and do not adequately display the tumor biology, additional selection parameters are emerging. Methods: Concise review of the current literature on patient selection for downstaging and LT for HCC outside the Milan criteria. Results: The major task in patients outside the Milan criteria is the need for higher granularity with patient selection, since the benefit through LT is not uniform. The recent literature clearly shows that beneath tumor size and number, additional selection parameters are useful in the process of patient selection for and during downstaging. For initial patient selection, the alpha fetoprotein (AFP) level adds additional information to the size and number of HCC nodules concerning the chance of successful downstaging and LT. This effect is quantifiable using newer selection tools like the WE (West-Eastern) downstaging criteria or the Metroticket 2.0 criteria. Also an initial PET-scan and/or tumor biopsy can be helpful, especially in the high risk group of patients outside the University of California San Francisco (UCSF) criteria. After this entry selection, the clinical course during downstaging procedures concerning the tumor and the AFP response is of paramount importance and serves as an additional final selection tool Conclusion: Selection criteria for liver transplantation in HCC patients are becoming more and more sophisticated, but are still imperfect. The implementation of molecular knowledge will hopefully support a more specific risk prediction for HCC patients in the future, but do not provide a profound basis for clinical decision-making at present.

CONTEXTO E OBJETIVO: O manejo do carcinoma hepatocelular (HCC) é desafiador devido a agressividade tumoral e cirrose associada. Faltam opções locais efetivas após falha à quimioembolização transarterial (TACE). Nosso objetivo foi testar através de estudo prospectivo fase II, a eficácia e segurança da Radioterapia Estereotáctica Corpórea (SBRT) em pacientes com HCC e resposta parcial ou contraindicação à TACE. MÉTODO: Pacientes com até 5 lesões de HCC restritas ao fígado realizaram SBRT na dose de 30 a 50 Gy em 5 frações. O desfecho primário foi sobrevida livre de progressão das lesões tratadas. Os desfechos secundários foram sobrevida livre de progressão hepática, sobrevida livre de progressão a distância, sobrevida global e toxicidade. Este estudo está registrado em clinicaltrials.gov sob o número NCT02221778. RESULTADO: De novembro de 2014 a junho de 2018, 19 pacientes receberam SBRT na dose mediana de 40 Gy (range 30 - 50 Gy). Todos tinham escore de Child Pugh A. A idade mediana foi de 67 anos (range 42-84 anos). A doença de base foi hepatite C em 42%, hepatite B em 26% e álcool em 26%. TACE prévia foi realizada em 84% dos pacientes, com mediana de duas TACEs (range 0-5). O número mediano de lesões foi dois (range 1-4), com tamanho mediano de 4 cm (1,5-10 cm). 32% dos pacientes tinham trombose tumoral; a AFP mediana pré-tratamento foi de 142,5 ng/ml (range 4,2 - 5 494 ng/ml). A sobrevida livre de progressão local em 1 ano foi de 80% (IC95%, 50% a 93%). A sobrevida livre de progressão hepática, sobrevida livre de progressão a distância e sobrevida global em 1 ano foram, respectivamente, de 52%, 82% e 84%. Não houve toxicidades clínicas grau 3 ou 4. Toxicidades laboratoriais até grau 3 ocorreram em 3 pacientes (16%). Resposta radiológica completa foi atingida em 53% dos pacientes, 42% tiveram resposta parcial. O tempo mediano para melhor resposta foi de 3,4 meses (range 2,4-12,6 meses). CONCLUSÃO: A SBRT é uma opção eficaz, segura e não invasiva em pacientes com HCC e resposta parcial ou contraindicação à quimioembolização / BACKGROUND AND PURPOUSE: Management of hepatocellular carcinoma (HCC) is challenging due to tumor aggressiveness and associated cirrhosis. There is paucity of effective local options after failure of transarterial chemoembolization (TACE). Our objective was to test in the setting of a phase II prospective study, the efficacy and safety of Stereotactic Body Radiation Therapy (SBRT) in patients with partial response or unsuitable for TACE. METHODS: Patients with HCC and up to five liver-only lesions received SBRT 30 to 50 Gy in 5 fractions. Primary endpoint was local progression-free survival. Secondary endpoints were liver progression-free survival, distant progression-free survival, overall survival and toxicity. This study is registered at clinicaltrials.gov NCT02221778. RESULTS: From Nov 2014 through Jun 2018, 19 patients received SBRT with a median dose of 40Gy (range 30 - 50 Gy). All patients were Child Pugh A. Median age was 67 years old (range 42-84y). Underlying liver disease was hepatitis C in 42% of patients, hepatitis B in 26% and alcohol-related in 26%. 84% received previous TACE, with a median of two TACEs (range 0-5). Patients had a median of two lesions (range 1-4), with median size of 4 cm (1.5-10 cm). 32% had tumor vascular thrombosis; median pretreatment AFP was 142.5 ng/ml (range 4.2 - 5,494 ng/ml). 1y local progression-free survival was 80% (95% CI, 50% to 93%). 1y liver progression-free survival, distant progression-free survival and overall survival were, respectively, 52%, 82% and 84%. No patient had clinical grade 3 or 4 toxicities. Laboratory toxicities up to grade 3 occurred in three patients (16%). Complete radiological response was seen in 53% of patients, 42% had partial response. Median time for best response was 3.4 months (range 2.4-12.6 months). CONCLUSION: SBRT is an effective, safe and noninvasive option in HCC patients with partial response or unsuitable for TACE

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Submitted by Irene Nascimento (irene.kessia@ufpe.br) on 2017-03-21T19:51:42Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE FINAL versão digital.pdf: 2839254 bytes, checksum: 962b7ff83b975bcd276b612274de7368 (MD5) / Made available in DSpace on 2017-03-21T19:51:42Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE FINAL versão digital.pdf: 2839254 bytes, checksum: 962b7ff83b975bcd276b612274de7368 (MD5) Previous issue date: 2016-08-15 / Facepe / Dentre os diversos procedimentos intervencionistas com fins terapêuticos, a quimioembolização hepática tem se destacado por ser de alta complexidade e resultar em altas doses de radiação aos pacientes e à equipe médica. Em alguns casos, o paciente requer várias sessões para tratar a mesma lesão, o que aumenta a probabilidade de ocorrência de lesões na pele e/ou efeitos estocásticos. Embora seja uma técnica altamente utilizada no Brasil, a quimioembolização não tem sido alvo de estudos dosimétricos. Este estudo apresenta os resultados da avaliação dosimétrica realizada na equipe médica e pacientes durante 109 procedimentos de quimioembolização hepática, realizados em seis serviços de hemodinâmica na cidade de Recife, Pernambuco. Os procedimentos foram realizados utilizando equipamentos de angiografia digital de diferentes fabricantes e tecnologias. A dosimetria dos pacientes foi caracterizada através das estimativas da máxima dose na pele (MDP), do produto kerma ar-área (PKA) e do kerma ar de referência (Ka,r). A MDP foi estimada a partir da utilização de filmes radiocrômicos do tipo Gafchromic XR RV3. Para avaliar o risco de efeitos estocásticos, foi estimada a dose absorvida em órgãos a partir de simulações Monte Carlo utilizando fantomas antropomórficos femininos e masculinos da serie FASH e MASH. Os resultados da dosimetria com filme radiocrômico mostraram valores da MDP variando de 180 a 5650 mGy; sendo que 40% dos pacientes apresentaram valores de dose na entrada da pele que ultrapassaram o limiar de dose para ocorrência de eritema transitório, que é de 2 Gy. O estudo das correlações entre a MDP, PKA e Ka,r mostrou que o Ka,r pode ser utilizado para avaliar a possibilidade de ocorrência de reações tissulares na pele dos pacientes submetidos a procedimentos de quimioembolização. Os resultados das simulações mostraram que alguns órgãos internos dos pacientes podem receber doses entre 500 mGy e 1 Gy. A dosimetria ocupacional foi realizada utilizando dosímetros termoluminescentes e dispositivos eletrônicos pessoais distribuídos em varias regiões do corpo dos profissionais. Os resultados mostraram que, com apenas uma quimioembolização por semana, o médico principal pode ultrapassar o limite anual de 20 mSv para o cristalino quando não são utilizados dispositivos de radioproteção como óculos ou telas de acrílico plumbíferos. O valor mais alto de equivalente de dose pessoal Hp(d) por procedimento medido no corpo do médico principal foi 5135,3 μSv no pé esquerdo. A ausência da cortina plumbífera durante a realização dos procedimentos é uma explicação para os valores altos registrados. Os valores médios de dose efetiva por procedimento para o médico principal, médico auxiliar e anestesista numa das instituições acompanhadas foram: 13 μSv, 6,1 μSv e 13,7 μSv, respectivamente. Estes resultados mostram que os níveis de exposição recebidos pelo anestesista em procedimentos de quimioembolização podem ser superiores aos do médico principal. Os resultados da dosimetria ocupacional com dosimetros eletrônicos mostraram que estes dispositivos podem ser utilizados de forma complementar na estimativa da dose ocupacional no cristalino em procedimentos de quimioembolização hepática. Nas seis instituições avaliadas observou-se uma alta variabilidade nos valores de dose no paciente e equipe médica, devido, principalmente, ao desempenho dos equipamentos, complexidade dos procedimentos, características físicas dos pacientes e experiência dos médicos. / Among interventional procedures, hepatic chemoembolization has been recognized as a complex procedure where high radiation doses to patients and medical staff are delivered. In some cases the patient has to endure several sessions to treat the same lesion, which increases even more the probability of skin injuries or stochastic effects. In Brazil, chemoembolization is widely used; however few dosimetric studies have been done so far. This study presents dosimetric results for medical staff and patients based on 109 hepatic chemoembolization procedures conducted in six hemodynamic departments in Recife, Pernambuco. The procedures were performed using digital angiography equipments from different manufacturers, using different technologies. Patient dosimetry comprised the measurement of the maximum skin dose (MSD), air kerma-area product (PKA) and reference air kerma (Ka,r). The MSD was measured using radiochromic films of type Gafchromic XR RV3. To assess the risk of stochastic effects, organ absorbed doses were calculated by Monte Carlo simulations using female and male anthropometric phantoms of the FASH and MASH series. MSDs between 180 and 5650 mGy were found based on the radiochromic film measurements. 40% of the patients monitored with radiochromic films received MSDs above the 2 Gy threshold for transient skin erythema. The findings of this study showed that the Ka,r can be used for risk estimates of tissue reactions in patients undergoing chemoembolization procedures. The Monte Carlo simulations showed that patients may receive organ doses between 500 mGy and 1 Gy. Occupational dosimetry was performed using thermoluminescent dosimeters and personal electronic devices distributed over various regions of the physician’s body. The results showed that the main operator could reach the annual limit of 20 mSv for the equivalent dose in the lens of the eyes with just one procedure per week if the radiation shields such as the ceiling suspended screen and goggles are not used. The highest values of personal dose equivalent Hp(d), measured in the body of the main operator was 5135.3 μSv in the left foot. Lack of table curtains explains the registered high values. Mean effective doses for the main operator, the auxiliary physician and the anesthesiologist in one of the institutions were 13 μSv, 6.1 μSv e 13.7 μSv, respectively. These results show that occupational doses received by the anesthesiologist in chemoembolization procedures may be higher than those received by the main operator. The results of the occupational dosimetry using electronic dosimeters showed that these devices can be used in a complementary way to estimate the occupational eye lens doses in hepatic chemoembolization procedures. High variability of radiation doses to patients and medical staff was observed among the six medical institutions, mainly because of the performance of X-ray equipments, complexity of the procedures, physical characteristics of the patients and the physician´s experience