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  • Author: Eleonora Molinaro x
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Laura Agate Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Francesca Bianchi Unit of Endocrine and Oncological Nuclear Medicine Therapy, Diagnostic and Imaging Department, University of Pisa, Pisa, Italy

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Federica Brozzi Unit of Endocrine and Oncological Nuclear Medicine Therapy, Diagnostic and Imaging Department, University of Pisa, Pisa, Italy

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Pierina Santini Unit of Endocrine and Oncological Nuclear Medicine Therapy, Diagnostic and Imaging Department, University of Pisa, Pisa, Italy

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Eleonora Molinaro Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Valeria Bottici Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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David Viola Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Loredana Lorusso Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Paolo Vitti Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Rossella Elisei Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Background: Recently, there has been a trend to reduce the use of radioiodine remnant ablation (RRA) in patients with low-risk (LR) and intermediate-risk (IR) differentiated thyroid cancer (DTC). Objectives: The aim of this paper was to evaluate the diagnostic role of whole-body scan (ptWBS) performed after RRA in LR and IR DTC patients. Methods: We analyzed 545 DTC patients treated with total thyroidectomy and RRA in hypothyroidism followed by a ptWBS. Neck ultrasound (US) and serum thyroglobulin measurement were performed. According to the American Thyroid Association guidelines, patients were classified as LR (n = 345) and IR (n = 200). Results: In addition to the thyroid remnant, the ptWBS showed the presence of further areas of <sup>131</sup>I uptake in 16/545 (2.9%) cases. ptWBS showed laterocervical lymph node metastases in 11/16 patients (10/11 were also detected by US), mediastinal uptake in 1/16, lung metastases in 3/16, and bone metastases in 1/16. Only 6/545 (1.1%) metastases were detected by ptWBS alone. After 7.8 years, 8/16 patients were free of disease, and 8 had persistent disease: 4 “biochemical” and 4 “structural.” Remission was achieved in 3 cases after one single <sup>131</sup>I course, in 1 case after surgery, and in the last 4 cases after several <sup>131</sup>I courses. Conclusions: The ptWBS diagnostic role was clinically relevant for the therapeutic strategies of our patients only in 1.1% of the cases. The cost-effectiveness of performing RRA and ptWBS in all LR and IR patients to find 1–2% of the cases with distant metastases remains controversial.

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Laura Valerio Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Carlotta Giani Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Laura Agate Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Eleonora Molinaro Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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David Viola Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Valeria Bottici Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Antonio Matrone Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Luciana Puleo Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Loredana Lorusso Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Virginia Cappagli Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Alessandro Ribechini Department of Thoracic Endoscopy, University Hospital of Pisa, Pisa, Italy

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Rossella Elisei Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Introduction: Tyrosine kinase inhibitors represent a better treatment in patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). Lenvatinib is usually well-tolerated, but sometimes, it is associated with serious and even life-threatening side effects. The aim of this study was to evaluate the prevalence of and the potential risk factors for fistula and/or organ perforation in RAI-R DTC patients treated with lenvatinib. Methods: This study included data from advanced and progressive RAI-R DTC patients treated with lenvatinib from February 2011 to February 2020 who were followed up at a single center. The clinical-pathological features and the biochemical and morphological results of the patients were collected at the time of starting lenvatinib and during the follow-up. Results: Fourteen of 95 (14.7%) locally advanced or metastatic RAI-R DTC patients treated with lenvatinib developed a fistula or organ perforation. Nine of 14 (64.3%) patients had tumor infiltration of the trachea, bronchus, esophagus, pleura, or bladder. Five of 14 (35.7%) had a bowel perforation, but only 2 had preexisting diverticulosis. Evaluation of the risk factors for developing a fistula or organ perforation showed that the presence of tumor infiltration and the tumor histology (papillary and poorly differentiated vs. follicular and Hurthle thyroid cancer) were significantly correlated with the development of a fistula or organ perforation (p = 0.003 and p = 0.02, respectively). In the subgroup of patients with tumor infiltration, we found that the papillary thyroid cancer histotype was the only potential predictor of fistula development. External beam radiation therapy (EBRT), the starting dose of lenvatinib, and the duration of treatment were not relevant for the development of fistula. Conclusions: In metastatic thyroid cancer patients treated with lenvatinib, the presence of tumor infiltration and histological type should be considered as potential risk factors for the development of fistula or organ perforation, although they do not represent an absolute contraindication. Although EBRT and the presence of diverticulosis were not significantly associated with the development of fistula and organ perforation, they should be regarded as potential additional reasons for the development of these complications. According to our findings, there is no reason to start lenvatinib at a lower daily dose when tumor infiltration is present.

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Carla Gambale Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Alessandro Prete Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Lea Contartese Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Liborio Torregrossa Department of Surgical, Medical, Molecular Pathology and Critical Area, Anatomic Pathology Section, University Hospital of Pisa, Pisa, Italy

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Francesca Bianchi Department of Nuclear Medicine, University Hospital of Pisa, Pisa, Italy

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Eleonora Molinaro Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Gabriele Materazzi Department of Surgical, Medical, Molecular Pathology and Critical Area, Unit of Endocrine Surgery, University Hospital of Pisa, Pisa, Italy

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Rossella Elisei Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Antonio Matrone Department of Clinical and Experimental Medicine, Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy

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Background

Second 131I treatment is commonly performed in clinical practice in patients with differentiated thyroid cancer and biochemical incomplete or indeterminate response (BiR/InR) after initial treatment.

Objective

The objective of the is study is to evaluate the clinical impact of the second 131I treatment in BiR/InR patients and analyze the predictive factors for structural incomplete response (SiR).

Patients and methods

One hundred fifty-three BiR/InR patients after initial treatment who received a second 131I treatment were included in the study. The clinical response in a short- and medium- long-term follow-up was evaluated.

Results

After the second 131I treatment (median 8 months), 11.8% patients showed excellent response (ER), 17% SiR, while BiR/InR persisted in 71.2%. Less than half (38.5%) of SiR patients had radioiodine-avid metastases. Patients who, following the second 131I treatment, experienced SiR had larger tumor size and more frequently aggressive histology and vascular invasion than those experienced BiR/InR and ER. Also, the median values of thyroglobulin on levothyroxine therapy (LT4-Tg), Tg peak after recombinant human TSH stimulation (rhTSH-Tg) and thyroglobulin antibodies (TgAb) were significantly higher in patients who developed SiR. At last evaluation (median: 9.9 years), BiR/InR persisted in 57.5%, while 26.2% and 16.3% of the patients showed ER and SiR, respectively. About half of BiR/InR patients (71/153 (46.4%)) received further treatments after the second 131I treatment.

Conclusions

Radioiodine-avid metastatic disease detected by the second 131I is an infrequent finding in patients with BiR/InR after initial treatment. However, specific pathologic and biochemical features allow to better identify those cases with higher probability of developing SiR, thus improving the clinical effectiveness of performing a second 131I treatment.

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Francesca Orsolini Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy

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Alessandro Prete Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy

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Pierpaolo Falcetta Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy

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Domenico Canale Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy

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Fulvio Basolo Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy

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Greta Alì Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy

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Francesca Manassero Division of Urology, Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy

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Paolo Vitti Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy

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Rossella Elisei Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy

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Eleonora Molinaro Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy

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Introduction

Medullary thyroid cancer (MTC) is a rare endocrine tumor, which can be sporadic or familial, as a component of multiple endocrine neoplasia 2 (MEN2). Overall, 10% of MTC cases have already developed at presentation or will develop metastasis during follow-up. Testicular metastases are exceptional and only one case of unilateral testis involvement by metastatic MTC has been already reported in literature. We described the first known case of asymptomatic bilateral testicular MTC metastases, discovered incidentally at testicular ultrasound (US) performed for unrelated reasons.

Case presentation

A Latin American 32-year-old man with MEN 2A syndrome and metastatic MTC underwent andrological and urological examination due to premature ejaculation. US imaging showed two symmetrical hypoechoic lesions involving both testes. Suspecting a bilateral testicular cancer, the patient underwent excision biopsy of both testicular lesions. Histopathology and immunohistochemical examinations documented metastatic MTC of both testicular lesions.

Conclusion

Beyond its rarity, testis should be considered as a potential metastatic site of MTC, especially in patients with advanced disease.

Established facts

  • Distant metastases are present at the diagnosis in 10–15% of patients with medullary thyroid carcinoma (MTC).

  • Testicular metastases are anecdotal. Only one case of unilateral testis involvement by metastatic MTC has been reported in the literature.

Novel insights

  • Testis should be considered as a possible site of metastases in patients with diffuse metastatic MTC.

  • Testicular ultrasound could be considered as an useful tool for the evaluation and follow-up of metastatic MTC.

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Elisa Minaldi E Minaldi, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Virginia Cappagli V Cappagli, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Loredana Lorusso L Lorusso, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Laura Valerio L Valerio, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Carlotta Giani C Giani, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Matilde Viglione M Viglione, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Laura Agate L Agate, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Eleonora Molinaro E Molinaro, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Antonio Matrone A Matrone, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Rossella Elisei R Elisei, Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Pisa, Italy

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Objective:

The aim of this study was to assess the clinical impact of hand-foot syndrome (HFS) during treatment with two multikinase inhibitors, sorafenib and lenvatinib, in a large group of patients with advanced thyroid cancer. Moreover, we looked for possible associations between HFS occurrence and clinical and pathological features.

Methods:

We retrospectively evaluated 239 patients with advanced thyroid cancer: 165 treated with lenvatinib and 74 with sorafenib. Statistical analysis was performed to verify which features could be correlated with HFS development.

Results:

HFS was observed in 35/74 (47.4%) and in 43/165 (26.7%) patients treated with sorafenib or lenvatinib, respectively. The median latency from the drug beginning and HFS appearance was 27 days for sorafenib and 2.9 months for lenvatinib. G3/G4 toxicity was observed in 16/35 (45.7%) patients treated with sorafenib and only in 3/43 (7%) treated with lenvatinib. Drug dose reduction due to HFS was required in 19/74 (25.7%) and 3/165 (1.8%) patients treated with sorafenib and lenvatinib, respectively. HFS occurrence was significantly associated with a longer duration of therapy in both groups.

Conclusions:

HFS was a frequent adverse event during both lenvatinib and sorafenib therapy, with a higher frequency and toxicity grade during sorafenib treatment. HFS was the most frequent reason for drug reduction or discontinuation in patient treated with sorafenib. Early diagnosis of HFS is important to allow early intervention, possibly in a multidisciplinary setting, and to avoid treatment discontinuation, which is highly relevant to obtain the maximum effectiveness of systemic therapy.

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Luciana Puleo Endocrine Unit, Department of Clinical and Experimental Medicine

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Laura Agate Endocrine Unit, Department of Clinical and Experimental Medicine

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Irene Bargellini Department of Vascular and Interventional Radiology

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Giuseppe Boni Regional Center of Nuclear Medicine

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Paolo Piaggi Endocrine Unit, Department of Clinical and Experimental Medicine

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Claudio Traino Regional Center of Nuclear Medicine

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Tommaso Depalo Regional Center of Nuclear Medicine

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Giulia Lorenzoni Department of Vascular and Interventional Radiology

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Francesca Bianchi Regional Center of Nuclear Medicine

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Duccio Volterrani Regional Center of Nuclear Medicine

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Sandra Brogioni Endocrine Unit, Department of Clinical and Experimental Medicine

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Valeria Bottici Endocrine Unit, Department of Clinical and Experimental Medicine

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Maurizia Rossana Brunetto Hepatology Unit, University of Pisa, Pisa, Italy

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Barbara Coco Hepatology Unit, University of Pisa, Pisa, Italy

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Eleonora Molinaro Endocrine Unit, Department of Clinical and Experimental Medicine

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Rossella Elisei Endocrine Unit, Department of Clinical and Experimental Medicine

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Objectives

Liver metastases occur in 45% of patients with advanced metastatic medullary thyroid cancer (MTC). Transarterial radioembolization (TARE) has been proposed to treat liver metastases (LM), especially in neuroendocrine tumors. The aim of this study was to investigate the biochemical (calcitonin and carcino-embryonic antigen) and objective response of liver metastases from MTC to TARE.

Methods

TARE is an internal radiotherapy in which microspheres loaded with β-emitting yttrium-90 (90Y) are delivered into the hepatic arteries that supply blood to LM. Eight patients with progressive multiple LM underwent TARE and were followed prospectively. They were clinically, biochemically and radiologically evaluated at 1, 4, 12 and 18 months after TARE.

Results

Two patients were excluded from the analysis due to severe liver injury and death due to extrahepatic disease progression, respectively. One month after TARE, a statistically significant (P = 0.02) reduction of calcitonin was observed in all patients and remained clinically relevant during follow-up; reduction of CEA, although not significant, was found in all patients. Significant reduction of liver tumor mass was observed 1, 4 and 12 months after TARE (P = 0.007, P = 0.004, P = 0.002, respectively). After 1 month, three of six patients showed partial response (PR) and three of six stable disease (SD) according to RECIST 1.1, while five of six patients had a PR and one of six a SD according to mRECIST. The clinical response remained relevant 18 months after TARE. Excluding one patient, all others showed only a slight and transient increase in liver enzymes.

Conclusions

TARE is effective in LM treatment of MTC. The absence of severe complications and the good tolerability make TARE a valid therapeutic strategy when liver LM are multiple and progressive.

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