Rodriguez-Fraile, M. (Macarena)

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    Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: a phase 2, single-arm study
    (Bmj, 2022) Reig, M. (Maria); Sangro, B. (Bruno); Testillano, M. (Milagros); Lledó, J.L. (José Luis); Iñarrairaegui, M. (Mercedes); Matilla, A. (Ana); Bilbao, J.I. (José I.); Da-Fonseca, L. (Leonardo); Márquez, L. (Laura); Rodriguez-Fraile, M. (Macarena); Lorente, S. (Sara); Varela, M.R. (María Rosario); Arenas, J.I. (Juan Ignacio); Torre-Aláez, M.A. (Manuel Antonio) de la; Argemí, J. (Josepmaria); Gómez-Martin, C. (Carlos)
    Purpose: To evaluate the safety and efficacy of selective internal radiation therapy (SIRT) in combination with a PD-1 inhibitor in patients with unresectable hepatocellular carcinoma (uHCC) and liver-only disease ineligible for chemoembolization. Patients and methods: NASIR-HCC is a single-arm, multicenter, open-label, phase 2 trial that recruited from 2017 to 2019 patients who were naïve to immunotherapy and had tumors in the BCLC B2 substage (single or multiple tumors beyond the up-to-7 rule), or unilobar tumors with segmental or lobar portal vein invasion (PVI); no extrahepatic spread; and preserved liver function. Patients received SIRT followed 3 weeks later by nivolumab (240 mg every 2 weeks) for up to 24 doses or until disease progression or unacceptable toxicity. Safety was the primary endpoint. Secondary objectives included objective response rate (ORR), time to progression (TTP), and overall survival (OS). Results: 42 patients received SIRT (31 BCLC-B2, 11 with PVI) and were followed for a median of 22.2 months. 27 patients discontinued and 1 never received Nivolumab. 41 patients had any-grade adverse events (AE) and 21 had serious AEs (SAE). Treatment-related AEs and SAEs grade 3-4 occurred in 8 and 5 patients, respectively. Using RECIST 1.1 criteria, ORR reported by investigators was 41.5% (95% CI 26.3% to 57.9%). Four patients were downstaged to partial hepatectomy. Median TTP was 8.8 months (95% CI 7.0 to 10.5) and median OS was 20.9 months (95% CI 17.7 to 24.1). Conclusions: The combination of SIRT and nivolumab has shown an acceptable safety profile and signs of antitumor activity in the treatment of patients with uHCC that were fit for SIRT.
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    Is a Technetium-99m Macroaggregated Albumin Scan Essential in the Workup for Selective Internal Radiation Therapy with Yttrium-90? An Analysis of 532 Patients
    (Elsevier, 2017) Sancho, L. (Lidia); Sangro, B. (Bruno); Iñarrairaegui, M. (Mercedes); Moran, V. (Verónica); Bilbao, J.I. (José I.); Rodriguez-Fraile, M. (Macarena); Beorlegui, C. (Carmen)
    Purpose: To determine if baseline patient, tumor, and pretreatment evaluation characteristics could help identify patients who require technetium-99m (99mTc) macroaggregated albumin (99mTc MAA) imaging before selective internal radiation therapy (SIRT). Materials and methods: In this retrospective analysis, 532 consecutive patients with primary (n = 248) or metastatic (n = 284) liver tumors were evaluated between 2006 and 2015. Variables were compared between patients in whom 99mTc MAA imaging results contraindicated/modified SIRT administration with yttrium-90 (90Y) resin microspheres and those who were treated as initially planned. The 99mTc MAA findings that contraindicated/modified SIRT were a lung shunt fraction (LSF) > 20%, gastrointestinal 99mTc MAA uptake, or a mismatch between 99mTc MAA uptake and intrahepatic tumor distribution. Results: LSF > 20% and gastrointestinal MAA uptake were observed in 7.5% and 3.9% of patients, respectively, and 11% presented a mismatch. Presence of a single lesion (odds ratio [OR] = 2.4) and vascular invasion (OR = 5.5) predicted LSF > 20%, and GI MAA uptake was predicted by the presence of liver metastases (OR = 3.7) and 99mTc MAA injection through the common/proper hepatic artery (OR = 4.7). Vascular invasion (OR = 4.1) was the only predictor of LSF > 20% and/or GI MAA uptake (sensitivity = 49.2%, specificity = 80.3%, negative predictive value = 92.4%). Previous antiangiogenic treatment (OR = 2.4) and presence of a single lesion (OR = 2.6) predicted mismatch. Conclusions: Imaging with 99mTc MAA is essential in SIRT workup because baseline characteristics may not adequately predict 99mTc MAA results. Nevertheless, the absence of vascular invasion potentially identifies a group of patients at low risk of SIRT contraindication/modification in whom performing SIRT in a single session (ie, pretreatment evaluation and SIRT on the same day) should be explored.
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    Exploring the Association Between Emphysema Phenotypes and Low Bone Mineral Density in Smokers with and without COPD
    (2020) Seijo, L. (Luis); Campo, A. (Arantza); Colina, I. (Inmaculada); Calleja, M. (María); Bertó, J. (Juan); Torres, J.P. (Juan P.) de; Alcaide, A.B. (Ana Belén); Rodriguez-Fraile, M. (Macarena); González, J. (Jessica); Rivera-Ortega, P. (Pilar); Restituto, P. (Patricia); Perez-Warnisher, M.T. (María Teresa); Zulueta, J. (Javier); Varo-Cenarruzabeitia, M.N. (Miren Nerea)
    Rationale: Emphysema and osteoporosis are tobacco-related diseases. Many studies have shown that emphysema is a strong and independent predictor of low bone mineral density (BMD) in smokers; however, none of them explored its association with different emphysema subtypes. Objective: To explore the association between the different emphysema subtypes and the presence of low bone mineral density in a population of active or former smokers with and without chronic obstructive pulmonary disease (COPD). Methods: One hundred and fifty-three active and former smokers from a pulmonary clinic completed clinical questionnaires, pulmonary function tests, a low-dose chest computed tomography (LDCT) and a dual-energy absorptiometry (DXA) scans. Subjects were classified as having normal BMD or low BMD (osteopenia or osteoporosis). Emphysema was classified visually for its subtype and severity. Logistic regression analysis explored the relationship between the different emphysema subtypes and the presence of low BMD adjusting for other important factors. Results: Seventy-five percent of the patients had low BMD (78 had osteopenia and 37 had osteoporosis). Emphysema was more frequent (66.1 vs 26.3%, p=<0.001) and severe in those with low BMD. Multivariable analysis adjusting for other significant cofactors (age, sex, FEV1, and severity of emphysema) showed that BMI (OR=0.91, 95% CI: 0.76–0.92) and centrilobular emphysema (OR=26.19, 95% CI: 1.71 to 399.44) were associated with low BMD. Conclusion: Low BMD is highly prevalent in current and former smokers. BMI and centrilobular emphysema are strong and independent predictors of its presence, which suggests that they should be considered when evaluating smokers at risk for low BMD.
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    Significant dose reduction is feasible in FDG PET/CT protocols without compromising diagnostic quality
    (Elsevier, 2018) Marti-Climent, J.M. (Josep María); Peñuelas-Sanchez, I. (Ivan); Sancho, L. (Lidia); Morales-de-Alava, I. (Isabel); Guillen, F. (Fernando); Prieto-Azcárate, E. (Elena); Richter, J.A. (José Ángel); Garcia-Velloso, M. J. (María José); Moran, V. (Verónica); García-García, B. (Berta); Rodriguez-Fraile, M. (Macarena)
    Purpose: To reduce the radiation dose to patients by optimizing oncological FDG PET/CT protocols. Methods: The baseline PET/CT protocol in our institution for oncological PET/CT examinations consisted of the administration of 5.18 MBq/kg of FDG and a CT acquisition with a reference current-time product of 120 mAs. In 2016, FDG activity was reduced to 4.44 and 3.70 MBq/kg and reference CT current-time-product was reduced to 100 and 80 mAs. 322 patients scanned with different protocols were retrospectively evaluated. For each patient, effective dose was calculated. The overall image quality was subjectively rated by the referring physician on a 4-point scale (IQ score: 1 excellent, 2 good, 3 poor but interpretable, 4 poor not interpretable). Image quality was quantitatively evaluated measuring noise in the liver. Results: CT Results: Effective dose was progressively reduced from 9.5 ± 2.8 to 8.0 ± 2.3 and 6.2 ± 1.5 mSv (p < 0.001). A mean dose reduction of 34.9% was achieved. There was a significant degradation of IQ score (p < 0.05) and noise (p < 0.001). Nevertheless, the number of poor quality studies (IQ score >2) did not increase. PET Results: Effective dose was gradually reduced from 6.5 ± 1.4 to 5.7 ± 1.3 and 5.0 ± 1.0 mSv (p < 0.001). Average dose reduction was 23.4%. IQ score (p < 0.05) and noise (p < 0.001) significantly degraded for lower activity protocols. However, all images with reduced activity were scored as interpretable (IQ score ≤ 3). Conclusions: A significant radiation dose reduction of 28.7% was reached. Despite a slight reduction in image quality, the new regime was successfully implemented with readers reporting unchanged clinical confidence.
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    Surgery and radioembolization of liver tumors
    (Elsevier, 2023) Rotellar, F. (Fernando); Sancho, L. (Lidia); Batidas, J.F. (Juan Fernando); Martinez-de-la-Cuesta, A. (Antonio); Rodriguez-Fraile, M. (Macarena); Aliseda, D. (Daniel)
    Surgical resection is considered the curative treatment par excellence for patients with primary or metastatic liver tumors. However, less than 40% of them are candidates for surgery, either due to nonmodifiable factors (comorbidities, age, liver dysfunction. . .), or to the invasion or proximity of the tumor to the main vascular requirements, the lack of a future liver remnant (FLR) adequate to maintain postoperative liver function, or criteria oftumor size and number. In these lastfactors, hepatic radioembolization has been shown to play a role as a presurgical tool, either by hypertrophy of the FLR or by reducing tumor size that manages to reduce tumor staging (term known as downstaging ¨ ¨ ). To these is added a third factor, which is its ability to apply the test oftime, which makes it possible to identify those patients who present progression of the disease in a short period of time (both locally and at distance), avoiding a unnecessary surgery. This paper aims to review RE as a tool to facilitate liver surgery, both through the experience of our center and the available scientific evidence.
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    Liver resection and transplantation following Yttrium-90 radioembolization for primary malignant liver tumors: a 15-year single-center experience
    (2023) Rotellar, F. (Fernando); Pardo-Sanchez, F. (Fernando); Ortega-Montes, A. (Ana); Lopez-Olaondo, L. (Luis); Benito-Boíllos, A. (Alberto); Zozaya-Larequi, G. (Gabriel); Hidalgo, F. (Francisco); Martinez-de-la-Cuesta, A. (Antonio); Sangro, B. (Bruno); Ponz-Sarvise, M. (Mariano); Iñarrairaegui, M. (Mercedes); Bilbao, J.I. (José I.); Herrero, J.I. (José Ignacio); Marti-Cruchaga, P. (Pablo); Rodriguez-Fraile, M. (Macarena); Rodríguez-Rodríguez, J. (Javier); Aliseda, D. (Daniel)
    Simple Summary Radioembolization is a locoregional therapy used in primary liver malignancies with different applications depending on the treatment goal. The aim of this retrospective study was to evaluate postoperative and long-term survival outcomes of patients with unresectable or high biological risk HCC and ICC treated with RE that were finally rescued to liver surgery with curative intent. In a cohort of 34 patients, we assessed that liver resection and transplantation after RE seem safe and feasible with adequate short-term outcomes. Moreover, long-term outcomes after RE and LR were optimal, with a 10-year OS rate greater than 50% for HCC and ICC patients. On the other hand, the 10-year OS rates from RE were also greater than 50% for patients with HCC downstaged or bridged to LT. Radioembolization (RE) may help local control and achieve tumor reduction while hypertrophies healthy liver and provides a test of time. For liver transplant (LT) candidates, it may attain downstaging for initially non-candidates and bridging during the waitlist. Methods: Patients diagnosed with HCC and ICC treated by RE with further liver resection (LR) or LT between 2005-2020 were included. All patients selected were discarded for the upfront surgical approach for not accomplishing oncological or surgical safety criteria after a multidisciplinary team assessment. Data for clinicopathological details, postoperative, and survival outcomes were retrospectively reviewed from a prospectively maintained database. Results: A total of 34 patients underwent surgery following RE (21 LR and 13 LT). Clavien-Dindo grade III-IV complications and mortality rates were 19.0% and 9.5% for LR and 7.7% and 0% for LT, respectively. After RE, for HCC and ICC patients in the LR group, 10-year OS rates were 57% and 60%, and 10-year DFS rates were 43.1% and 60%, respectively. For HCC patients in the LT group, 10-year OS and DFS rates from RE were 51.3% and 43.3%, respectively. Conclusion: Liver resection after RE is safe and feasible with optimal short-term outcomes. Patients diagnosed with unresectable or high biological risk HCC or ICC, treated with RE, and rescued by LR may achieve optimal global and DFS rates. On the other hand, bridging or downstaging strategies to LT with RE in HCC patients show adequate recurrence rates as well as long-term survival.
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    Computational study of the microsphere concentration in blood during radioembolization
    (2022) Aramburu-Montenegro, J. (Jorge); Sangro, B. (Bruno); Lertxundi-Ferrán, U.(Unai); Rodriguez-Fraile, M. (Macarena); Antón-Remírez, R. (Raúl)
    Computational fluid dynamics techniques are increasingly used to computer simulate radioembolization, a transcatheter intraarterial treatment for patients with inoperable tumors, and analyze the influence of treatment parameters on the microsphere distribution. Ongoing clinical research studies are exploring the influence of the microsphere density in tumors on the treatment outcome. In this preliminary study, we computationally analyzed the influence of the microsphere concentration in the vial on the microsphere concentration in the blood. A patient-specific case was used to simulate the blood flow and the microsphere transport during three radioembolization procedures in which the only parameter varied was the concentration of microspheres in the vial and the span of injection, resulting in three simulations with the same number of microspheres injected. Results showed that a time-varying microsphere concentration in the blood at the outlets of the computational domain can be analyzed using CFD, and also showed that there was a direct relationship between the variation of microsphere concentration in the vial and the variation of microsphere concentration in the blood. Future research will focus on elucidating the relationship between the microsphere concentration in the vial, the microsphere concentration in the blood, and the final microsphere distribution in the tissue.
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    3D voxel-based dosimetry to predict contralateral hypertrophy and an adequate future liver remnant after lobar radioembolization
    (Springer, 2021) Sancho, L. (Lidia); Prieto-Azcárate, E. (Elena); Sangro, B. (Bruno); Iñarrairaegui, M. (Mercedes); Grisanti-Vollbracht, F. (Fabiana); Bastidas, J.F. (Juan Fernando); Bilbao, J.I. (José I.); Rodrigo, P. (Pablo); Rodriguez-Fraile, M. (Macarena); Beorlegui, C. (Carmen)
    Introduction Volume changes induced by selective internal radiation therapy (SIRT) may increase the possibility of tumor resection in patients with insufficient future liver remnant (FLR). The aim was to identify dosimetric and clinical parameters associated with contralateral hepatic hypertrophy after lobar/extended lobar SIRT with 90Y-resin microspheres. Materials and methods Patients underwent 90Y PET/CT after lobar or extended lobar (right + segment IV) SIRT. 90Y voxel dosimetry was retrospectively performed (PLANET Dose; DOSIsoft SA). Mean absorbed doses to tumoral/non-tumoral-treated volumes (NTL) and dose-volume histograms were extracted. Clinical variables were collected. Patients were stratified by FLR at baseline (T0-FLR): < 30% (would require hypertrophy) and ≥ 30%. Changes in volume of the treated, non-treated liver, and FLR were calculated at < 2 (T1), 2–5 (T2), and 6–12 months (T3) post-SIRT. Univariable and multivariable regression analyses were performed to identify predictors of atrophy, hypertrophy, and increase in FLR. The best cut-off value to predict an increase of FLR to ≥ 40% was defined using ROC analysis. Results Fifty-six patients were studied; most had primary liver tumors (71.4%), 40.4% had cirrhosis, and 39.3% had been previously treated with chemotherapy. FLR in patients with T0-FLR < 30% increased progressively (T0: 25.2%; T1: 32.7%; T2: 38.1%; T3: 44.7%). No dosimetric parameter predicted atrophy. Both NTL-Dmean and NTL-V30 (fraction of NTL exposed to ≥ 30 Gy) were predictive of increase in FLR in patients with T0 FLR < 30%, the latter also in the total cohort of patients. Hypertrophy was not significantly associated with tumor dose or tumor size. When ≥ 49% of NTL received ≥ 30 Gy, FLR increased to ≥ 40% (accuracy: 76.4% in all patients and 80.95% in T0-FLR < 30% patients). Conclusion NTL-Dmean and NTL exposed to ≥ 30 Gy (NTL-V30) were most significantly associated with increase in FLR (particularly among patients with T0-FLR < 30%). When half of NTL received ≥ 30 Gy, FLR increased to ≥ 40%, with higher accuracy among patients with T0-FLR < 30%.
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    Nuevos horizontes en cirugía mamaria. Cirugía radioguiada y biopsia selectiva de ganglio centinela
    (Ediciones Universidad de Navarra, 2008) Valero, M. (Marta); Garcia-Manero, M. (Manuel); Lopez-Garcia, G. (Guillermo); Richter, J.A. (José Ángel); Rodriguez-Fraile, M. (Macarena)
    Although needle-wire localization is the most commonly used localization technique for nonpalpable breast lesion biopsy, the technique of radioguided occult lesion localization (ROLL), is becoming increasingly used for open-surgery diagnosis in such cases. Sentinel lymph node biopsy(SLNB) is based on the hypothesis that lymphatic drainage from a tumor reaches the sentinel node(SLN) first and that it can be identified accurately and removed. If SLN exactly reflects the lymph-node status, a negative SLN for metastasis might allow complete axillary lymph node dissection (ALDN) to be avoided.
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    Impact of the dosimetry approach on the resulting 90Y radioembolization planned absorbed doses based on 99mTc-MAA SPEC T-CT: is there agreement between dosimetry methods?
    (2020) Zubiria, A. (Arantxa); Prieto, E. (Elena); Marti-Climent, J.M. (Josep María); Sancho, L. (Lidia); Soria, L. (Leticia); Moran, V. (Verónica); Rodriguez-Fraile, M. (Macarena)
    Background: Prior radioembolization, a simulation using 99mTc-macroaggregated albumin as 90Y-microspheres surrogate is performed. Gamma scintigraphy images (planar, SPECT, or SPECT-CT) are acquired to evaluate intrahepatic 90Y-microspheres distribution and detect possible extrahepatic and lung shunting. These images may be used for pre-treatment dosimetry evaluation to calculate the 90Y activity that would get an optimal tumor response while sparing healthy tissues. Several dosimetry methods are available, but there is still no consensus on the best methodology to calculate absorbed doses. The goal of this study was to retrospectively evaluate the impact of using different dosimetry approaches on the resulting 90Y-radioembolization pre-treatment absorbed dose evaluation based on 99mTc-MAA images. Methods: Absorbed doses within volumes of interest resulting from partition model (PM) and 3D voxel dosimetry methods (3D-VDM) (dose-point kernel convolution and local deposition method) were evaluated. Additionally, a new “Multi-tumor Partition Model” (MTPM) was developed. The differences among dosimetry approaches were evaluated in terms of mean absorbed dose and dose volume histograms within the volumes of interest. Results: Differences in mean absorbed dose among dosimetry methods are higher in tumor volumes than in non-tumoral ones. The differences between MTPM and both 3D-VDM were substantially lower than those observed between PM and any 3D-VDM. A poor correlation and concordance were found between PM and the other studied dosimetry approaches. DVH obtained from either 3D-VDM are pretty similar in both healthy liver and individual tumors. Although no relevant global differences, in terms of absorbed dose in Gy, between both 3D-VDM were found, important voxel-by-voxel differences have been observed. Conclusions: Significant differences among the studied dosimetry approaches for 90Y-radioembolization treatments exist. Differences do not yield a substantial impact in treatment planning for healthy tissue but they do for tumoral liver. An individual segmentation and evaluation of the tumors is essential. In patients with multiple tumors, the application of PM is not optimal and the 3D-VDM or the new MTPM are suggested instead. If a 3D-VDM method is not available, MTPM is the best option. Furthermore, both 3D-VDM approaches may be indistinctly used.