Peptide receptor radionuclide therapy with [177Lu]Lu-DOTA-TATE | Revista Española de Medicina Nuclear e Imagen Molecular (English Edition)

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Prado-Wohlwend, J.C. Bernal-Vergara, A. Utrera-Costero, J.R. Cañón-Sánchez, M. Agudelo-Cifuentes, P. Bello-Arques" "autores" => array:7 [ 0 => array:4 [ "nombre" => "S." "apellidos" => "Prado-Wohlwend" "email" => array:1 [ 0 => "prado_ste@gva.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "J.C." "apellidos" => "Bernal-Vergara" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Utrera-Costero" ] 3 => array:2 [ "nombre" => "J.R." "apellidos" => "Cañón-Sánchez" ] 4 => array:2 [ "nombre" => "M." "apellidos" => "Agudelo-Cifuentes" ] 5 => array:2 [ "nombre" => "P." "apellidos" => "Bello-Arques" ] 6 => array:1 [ "colaborador" => "on behalf of the Endocrinology Working Group of the SEMNIM" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Terapia con péptidos radiomarcados con [177Lu]Lu-DOTA-TATE" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1761 "Ancho" => 2500 "Tamanyo" => 279049 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Mechanism of action of [177Lu]Lu-DOTA-TATE." ] ] ] "textoCompleto" => "Introduction to neuroendocrine tumors and the concept or teragnosisNeuroendocrine tumors (NET) are a group of epithelial neoplasms arising from neuroendocrine cells which, during the embryonic stage, are distributed through the neural crest, the endocrine glands, pancreatic islets, and the diffuse endocrine system. NET cells are structured in the form of glandular, trabecular, or solid nests and produce abundant neurosecreting granules expressed by immunohistochemical markers such as chromogranin A (CgA), synaptophysin and specific neuronal enolase. Although they may originate in any localization, the most common are gastroenteropancreatic (GEP) (66%) and pulmonary (31%), being less frequent on the skin, in adrenal or thyroid glands and the urogenital tract. These tumors are complex due to the heterogeneity of their clinical presentation, the need to use multiple tests to obtain a diagnosis and the possibility of applying different systemic and targeted therapies requiring multidisciplinary teams for their diagnosis, follow-up, and personalized management.While these tumors are infrequent, their incidence has increased, being estimated as 6.8 cases per 100,000 inhabitants, probably due to the advances in diagnostic techniques and the more generalized use of multimodal imaging<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a>. NET can be classified based on their histological and immunohistochemical characteristics. The World Health Organization divides GEP-NET according to their proliferation index (Ki-67), mitotic rate and grade of cellular differentiation. NET of pulmonary and thymus origin are classified in a similar way but without using the Ki-67 index<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Mixed neoplasias correspond to tumors with a non-endocrine and a neuroendocrine component that is generally neuroendocrine cancer. These must be genotypically related tumors and the neuroendocrine component must correspond to at least 30% of the tumor. Whenever possible, each component should be classified separately.Paragangliomas (PG) and pheochromocytomas (PCC) are less common types of NET with an annual incidence of 1/300,000. The PG originate in the autonomous extra-adrenal paraganglia, and PCC are from the adrenal medulla. The paraganglia are small organs mainly made up of neuroendocrine cells derived from the embryonic neural crest and together with PCC can secrete catecholamines and produce hormonal syndromes.Another way to classify NET is as functioning and non-functioning tumors, based on the presence or not of a clinical syndrome produced by hormone secretion.Most pancreatic NET are non-functioning, and in the small percentage of functioning tumors the secretion varies based on the pancreatic islet cells from which it is derived and may include gastrinomas, insulinomas, glucagonomas, VIpomas or somatostatinomas. NET of intestinal origin may also be functioning tumors producing a carcinoid syndrome mainly due to the secretion of serotonin<a class="elsevierStyleCrossRef" href="#bib0025">5</a>.Despite their heterogeneity in the tissue of origin, NET share the expression of neuroendocrine immunohistochemical markers which facilitate the secretion of bioactive peptides such as CgA, serotonin, gastrin, and insulin. The release of these substances is regulated by somatostatin (SS), which is an oligopeptide that is produced endogenously, mainly in the central nervous system. This peptide interacts with the somatostatin transmembrane receptors (SSTR) of the cell surface, which are present in more than 80% of NET<a class="elsevierStyleCrossRef" href="#bib0030">6</a>.Up to five subtypes of SS receptors have been identified: SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5. The expression of the SSTR may vary among the different NET, having a wide distribution in the different tissues and presenting several subtypes in the same tumor. However, SSTR2 followed by SSTR5 are the most frequently associated with NET. Overexpression of these receptors, especially SSTR2, regarding healthy tissue is the cornerstone for the development of the theragnosis in these tumors<a class="elsevierStyleCrossRefs" href="#bib0035">7–9</a>.The concept of theragnosis refers to the possibility of using molecules with specific affinity for determined tumors for both their diagnosis and treatment. It is a developing field that allows, accurate personalized oncological treatment.Among the theragnostic radiopharmaceuticals used in NET, those using SSTR as a target stand out. They are made up of three parts: a radioactive metal (68Ga, 111In and 99mTc for diagnosis and 177Lu or 90Y for treatment), a peptide analog with affinity for the membrane SSTR (TOC, TATE and NOC) and a chelator that both binds and stabilizes the radioactive metal to avoid their dissociation in vivo (DOTA and DPTA) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The treatment of NET with radioisotopes is also called peptide receptor radionuclide therapy (PRRT) and can be performed with two radiopharmaceuticals: [177Lu]Lu-DOTA-TATE (PRRT-Lu) and [90Y]Y-DOTA-TOC (PRRT-Y). We will focus on the first since it is the only one for which we have authorization.Key point:The concept of theragnosis refers to the possibility of using molecules with specific affinity for determined tumors for both their diagnosis and treatment.Functional imaging studies in the theragnosis of neuroendocrine tumorsRadiopharmaceuticals that detect the expression of somatostatin receptorsThe intense overexpression of SSTR in the cellular membrane of a large number of NET constitutes the basis of the use of functional imaging studies for their diagnosis. Confirmation of this overexpression is essential to consider PRRT<a class="elsevierStyleCrossRef" href="#bib0050">10</a>.Functional imaging studies of SSTR may include:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-Scintigraphy and single photon emission computed tomography/computerized tomography (SPECT/CT) of SSTR (SPECT/CT-SSTR) such as [111In]octreotide (OctreoScan®) and [99mTc]Tc-HYNIC-TOC (Tektrotyd®). For years these techniques have been considered the gold standard of functional imaging despite having certain limitations with respect to the new positron emission tomography (PET)/CT as well as lesser sensitivity due to their lower spatial resolution.</li><li class="elsevierStyleListItem" id="lsti0010">-PET/CT-SSTR with [68Ga]-DOTA-TOC/TATE/NOC.</li></ul>PET/CT-SSTR studies require a shorter waiting and acquisition time, reduce the dosimetry of the patient, allow quantification of uptake, and by being performed earlier, present less biliary elimination<a class="elsevierStyleCrossRef" href="#bib0055">11</a>. The TOC and TATE analogs show a high affinity for SSTR2 and SSTR5, while NOC has less affinity for SSTR2 but has an additional binding to the SSTR3 and SSTR5. The three labeled with 68Ga are currently widely used in routine clinical practice<a class="elsevierStyleCrossRefs" href="#bib0060">12,13</a>.The condition necessary to administer PRRT is confirmation of elevated SSTR expression in functional imaging studies. To characterize the intensity of uptake in both scintigraphy SPECT/CT studies and PET/CT, the qualitative Krenning scale is usually used with numerical values from 0 to 4. This scale was initially described for planar scintigraphy of SSTR, but it was later validated for PET/CT-SSTR. In PET/CT-SSTR a significantly higher level of uptake has been observed in the Krenning scale than in planar imaging and SPECT/CT, especially in lesions of less than 2 cm. The intensity of uptake in the functional SSTR images should be integrated with the diameter and the extension of the tumor to optimize the selection of candidates to PRRT<a class="elsevierStyleCrossRef" href="#bib0070">14</a>. As in other tumors, to do this a structured SSTR-RADS reporting system has been proposed and is applied in the theragnosis of NET. In this report the intensity of uptake in the functional image of SSTR is correlated with the localization (typical or atypical), the findings of the conventional images and the presence or not of a previous biopsy. Patients with a Krenning score greater than or equal to 3 and SSTR-RADS greater than or equal to 4 are candidates for PRRT<a class="elsevierStyleCrossRef" href="#bib0075">15</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>[18F]fluorodeoxyglucose PET/CTPET/CT-SSTR should not be the only functional image to evaluate in NET. PET/CT-SSTR and PET/CT with [18F]fluorodeoxyglucose (18F-FDG) should be carried out as an integrated strategy in NET which are not of low grade (G1). In general, the uptake of PET/CT-SSTR is greater in low-grade NET (G1 and G2), while the avidity for a metabolic tracer such as 18F-FDG is higher in G2 and G3 NET. 18F-FDG-PET/CT allows evaluation of the state of dedifferentiation and the prognosis. The combination of the avidity of 18F-FDG-PET/CT and the lack of avidity in PET/CT-SSRT may indicate the presence of a more aggressive, high-grade NET that is not a candidate for PRRT and has a worse prognosis. To the contrary, a PET/CT-SSTR with avidity in all the known lesions with 18F-FDG uptake likely corresponds to low-grade disease, with a more indolent course, better prognosis, and candidate to PRRT. In addition, there may be significant tumoral heterogeneity in the same patient, with the coexistence of well differentiated and poorly differentiated lesions<a class="elsevierStyleCrossRef" href="#bib0080">16</a>.[123I]Metaiodobenzylguanidine scintigraphy-SPECT/CTThis is an imaging study with theragnostic implications in PCC and PG (and to a lesser, extent medullary thyroid cancer). It is not used to plan PRRT but rather to determine the expression of norepinephrine transporters (NT) and evaluate the alternative therapeutic option with [131I]Metaiodobenzylguanidine (MIBG). In these patients both SSTR and NT expression should be assessed to select the best therapeutic target. If greater or equal avidity of the lesions is observed by [123I]MIBG than by SSTR, [131I]MIBG should be administered. If the avidity is greater by the SSTR, the choice should be PRRT<a class="elsevierStyleCrossRef" href="#bib0085">17</a>.Key point:PET/CT-SSTR and 18F-FDG-PET/CT should be carried out as an integrated imaging strategy in NET which are not low-grade. In general, the uptake of PET/CT-SSTR is greater in low-grade NET (G1 and G2), while the avidity for a metabolic radiotracer such as 18F-FDG is higher in G2 and G3 NET.Therapy with peptides radiolabeled with [177Lu]Lu-DOTA-TATEFirst line pharmacological treatment in well differentiated metastatic or inoperable NET that express SSTR involves somatostatin analogs (SSA). These analogs reduce the symptomatology derived from hormone hypersecretion and also have an antiproliferative effect. When the disease progresses, other systemic therapies are available for SSA, such as everolimus, sunitinib, cytotoxic chemotherapy and PRRT. Among these, PRRT-Lu allows the selective administration of high doses of radiation to the tissues that overexpress SSTR with minimal systemic toxicity<a class="elsevierStyleCrossRef" href="#bib0090">18</a>.Objective, indications, and patient selectionAlthough the ideal objective would be complete disease remission, the real objectives of PRRT are: to stabilize the disease, reduce local and secretory symptoms, and improve the quality of life of the patients.In Spain, [177Lu]Lu-DOTA-TATE (Lutathera®) was authorized by the Spanish Agency of Medications and Medical Devices (AEMPS) for PRRT in January 2018. It is indicated in patients with metastatic or inoperable GEP-NET with overexpression of SSTR and well differentiated (G1 and G2).All the patients who are candidates for this therapy should be evaluated by an expert multidisciplinary clinical committee to determine whether the patient fulfills the criteria for this treatment with the least adverse effects possible.Key point:In Spain, the indication for PRRT with con [177Lu]Lu-DOTA-TATE authorized by AEMPS is for metastatic or inoperable GEP-NET with overexpression of SSTR and well differentiated (grade 1 and 2). The decision of administration should always be made by a multidisciplinary committee with expertise in NET, and this is especially important is patients who may be more sensitive to its adverse effects.Mechanism of actionThe radiopharmaceutical [177Lu]Lu-DOTA-TATE is formed by a semisynthetic SSA that has high affinity for SSTR2. It binds to a β-emitter radioactive isotope (177Lu) with an energy of 0.497 MeV, range of 20 cells in diameter, maximum tissue penetration of 2.2 mm (mean 0.67 mm) and a semidecay time of 6.647 days. In addition, it is associated with an emission of γ radiation of 113 keV and 208 keV, which allows acquiring scintigraphy and SPECT/CT images post-treatment.[177Lu]Lu-DOTA-TATE binds to the SSTR2 that are overexpressed in NET, is internalized and remained trapped in the lysosomes. Its radiation produces cell death by rupture of the DNA chains. It is scarcely metabolized and is mainly excreted in the urine (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Selection of patients who are candidates to therapyCandidate patients are those with metastatic or inoperable NET in progression to SSA, with a Karnofsky scale >60% or Eastern Cooperative Oncology Group score <2 and who fulfill the following characteristics:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015">-PET/CT-SSTR or SPECT/CT-SSTR:</li></ul>Overexpression of somatostatin receptors in lesions with an intensity of uptake ≥3 in the Krenning scale (greater than the liver).Tumors with a lower intensity of uptake (Krenning 1 and 2), or who present greater avidity for 18F-FDG than for SSTR imaging are not good candidates for treatment<a class="elsevierStyleCrossRef" href="#bib0095">19</a>. <ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0020">-Analytical requirements:</li></ul>Hemoglobin >8 g/dL, red blood cells > 3000/μL.Leucocytes >3000/μL, neutrophils >1000/μL.Platelets >75 × 10^3/µL.Bilirubin <3 times the high limit of normality.Serum albumin >30 g/L. If albumin values are <30 g/L, the prothrombin time must be normal.Glomerular filtration rate (GFR) >50 mL/min. The radiopharmaceutical can be administered in patients on dialysis.Contraindications to treatmentAbsolute: pregnancy, myelosuppression, and life expectancy less than 6 months.Relative: breast feeding, renal insufficiency, hematological toxicity without myelosuppression, patients less than 18 years of age and carcinoid cardiopathy.Special situations<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0025">-Renal insufficiency: PRRT-Lu has shown to be safe in patients with renal insufficiency. Precaution is recommended in patients on hemodialysis or with severe renal insufficiency (GFR < 30), in whom a reduction in the activity administered may be an option. It is recommended to treat cases of hydronephrosis prior to undergoing PRRT<a class="elsevierStyleCrossRef" href="#bib0100">20</a>.</li><li class="elsevierStyleListItem" id="lsti0030">-Previous chemotherapy: there is insufficient evidence regarding the increase of risk of myelodysplasia and acute leukemia with PRRT in patients who have previously undergone cytotoxic chemotherapy.</li><li class="elsevierStyleListItem" id="lsti0035">-Peritoneal and mesenteric carcinomatosis: it is recommended to evaluate the administration of corticosteroids to prevent local inflammation and even intestinal obstruction.</li><li class="elsevierStyleListItem" id="lsti0040">-Pediatric age: it may be useful, especially in cases of PG and PCC.</li></ul>Patient preparation, activity, and protocol of administrationPrevious medical consultation with a nuclear medicine physician is recommended to explain the procedure, the characteristics of the treatment, the measures of radiological protection and to sign the informed consent.Treatments which may diminish the uptake of [177Lu]Lu-DOTA-TATE must be withdrawn:<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0045">-SSA: 4–6 weeks if of prolonged action and at least 24 h for those of short action. They may be reinitiated 4–24 h after each treatment cycle.</li><li class="elsevierStyleListItem" id="lsti0050">-Chemotherapy, interferon, antiangiogenics: 4–6 weeks.</li><li class="elsevierStyleListItem" id="lsti0055">-Everolimus: 10 days before.</li></ul>A total of 4 treatment cycles are administered, separated by 8–10 weeks, with a recommended dose of 7.4 GBq (200 mCi). In patients with hematological toxicity, the use of half the dose is recommended (3.7 GBq). If this resolves in the following 16 weeks, the treatment may be continued with the standard activity.Although there may be small differences among the centers performing this therapy, an example of the administration protocol is described below:The patient is admitted to the metabolic therapy unit; the weight, height and vital signs are registered; the venous access is prepared, and the protocol is initiated (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0060">-Minute 0: premedication with antiemetics (for example, ondansetron 4−8 mg) to prevent vomiting secondary to the metabolic acidosis produced by the administration of amino acids (aa) and may be maintained every 8 h during admission. This effect is significantly reduced if a master formula composed of lysine and arginine is used instead of a commercial formula.</li><li class="elsevierStyleListItem" id="lsti0065">-Minute 30: begin the infusion of aa (2.5% of lysine and 2.5% of arginine) in 1 L of water for injection during a minimum of 4 h to prevent renal toxicity, and for reabsorption of the radiopharmaceutical in the proximal convoluted tubule. If the concentration indicated above is not available in the preparation center, commercial preparations which best adjust to the desired arginine and lysine concentrations can be used.</li><li class="elsevierStyleListItem" id="lsti0070">-Minute 60: begin the administration of [177Lu]Lu-DOTA-TATE, 50 mL over 30 min.</li><li class="elsevierStyleListItem" id="lsti0075">-Minute 90: maintain the aa infusion until completing the total infusion time. To minimize the dose of radiation to the bladder, encourage hydration during the remainder of the admission. In patients with carcinoid cardiopathy the infusion volume can be reduced, and the length of infusion lengthened to avoid volume overload.</li></ul><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Criteria of discharge and treatment controlApproximately 50% of the activity of [177Lu]Lu-DOTA-TATE administered is eliminated by the urinary tract in the first 6 h. Based on the calculations of radiation exposure using total body clearance and exposure rate to one meter in 24 h, it has been described that patients may be treated on an outpatient basis<a class="elsevierStyleCrossRef" href="#bib0105">21</a>. In some centers the patients remain admitted for 24 h follow-up, control of vital signs, rapid identification of adverse effects and acquisition of images of post-treatment distribution.Between 4 and 24 h after the administration of the radiopharmaceutical, a whole body distribution scan (medium energy collimator, phototopic 113 and 208 keV) is performed to evaluate the concordance of the uptakes of [177Lu]Lu-DOTA-TATE with the tumoral lesions described in the SSTR diagnostic studies. The 24 h image has less background activity and better quality, which is more manifested in areas of physiological uptake such as the liver. In the case of the presence of small sized liver involvement it is useful to obtain 24 h images and SPECT/CT to improve the localization of the lesions. In addition, SPECT/CT allows performing dosimetric studies (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>Follow-up and evaluation of responseThe follow-up of these patients is focused on the clinical symptoms, imaging techniques, analytical findings and tumoral biomarkers.In general, in GEP and pulmonary G1 and G2 NET an initial clinical follow-up of imaging and biomarkers is recommended every 3 months. In confirmed stable disease or slow growth after 15 months, imaging controls can be made every 6–12 months and clinical and biomarker controls every 3–6 months. Patients with aggressive lesions or of rapid progression should continue with imaging controls every 3 months.The frequency of controls should be increased in patients with risk factors such as high-grade tumors, elevated tumoral load, wide-spread disease, aggressive behavior, severe endocrine symptoms, weight loss or clinical worsening and CgA levels more than 10-fold the normal values<a class="elsevierStyleCrossRef" href="#bib0110">22</a>.Analytical follow-up and tumoral biomarkersThe European Association of Nuclear Medicine guidelines recommend performing an analytical control at 2, 4 and 6 weeks after every treatment including liver and renal function tests and hemogram to determine if it is adequate to continue with the administration of the next dose. Once the fourth cycle has been completed, the controls are made every 8–12 weeks during the first 12 months followed by twice a year thereafter.The following are among the tumoral biomarkers most frequently used in patient follow-up:<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0080">-CgA: most frequently used in G1 and G2. This biomarker indicates changes in tumoral load and secretory activity. It is a prognostic indicator in small intestine NET and of possible recurrences. It may be elevated in the absence of disease (IBPs proton pump inhibitor, chronic gastritis, renal insufficiency).</li><li class="elsevierStyleListItem" id="lsti0085">-CgB: for the follow-up of rectal and pulmonary NET.</li><li class="elsevierStyleListItem" id="lsti0090">-5-hydroxyindoleacetic acid (5-HIAA): in NET of the small intestine, appendix, and serotonin-producing pulmonary NET, especially those with carcinoid syndrome. It may be altered by some foods.</li><li class="elsevierStyleListItem" id="lsti0095">-Gastrointestinal hormones: in functioning pancreatic-duodenal NET the hormone produced is used as a biomarker, although its prognostic value is not clear.</li><li class="elsevierStyleListItem" id="lsti0100">-Brain natriuretic peptide: every one or two years in patients with carcinoid syndrome to detect the appearance of carcinoid cardiopathy.</li></ul>Follow-up by imagingAbdominopelvic thoracic CT with a 3-phase hepatic study is the preferred conventional imaging technique. An abdominal magnetic resonance study may be considered in the follow-up of hepatic lesions and in young patients to reduce the radiation dose. The functional imaging studies include performing SSTR studies (SPECT/CT-SSTR or PET/CT-SSTR) and in G2-G3 NET 18F-FDG-PET/CT, and both may be carried out based on the characteristics of the patient.The evaluation of response to treatment is complex due to the particular characteristics of NET, such as their high vascularization, and the changes produced by targeted therapies such as PRRT.The Response Evaluation Criteria in Solid Tumors (RECIST) criteria may be suboptimal because they do not show the cystic or necrotic changes produced within the tumor. As an alternative, the CHOI criteria have been considered, which, in addition to size, introduce the attenuation of the tumor in Hounsfield Units (HU) and have shown better adjustment to overall survival (OS) in patients with response to PRRT compared to the RECIST criteria<a class="elsevierStyleCrossRefs" href="#bib0115">23,24</a>. The PET Response Criteria in Solid Tumors (PERCIST) have not yet been standardized for evaluating the response of NET by PET/CT-SSTR. The main indications of molecular imaging in the follow-up of NET are the presence of a clinical-biochemical-morphological dissociation and consideration of PRRT with the aim of optimizing the imaging studies and radiation received by the patient.Key point:The RECIST criteria may be suboptimal because they do not demonstrate the cystic or necrotic changes produced within the tumor. As an alternative, the CHOI criteria have been considered, which, in addition to size, introduce the attenuation of the tumor in HU and have shown better adjustment to overall survival in patients with response to PRRT compared to the RECIST criteria.Adverse eventsIn general, adverse events are mild, self-limiting and well tolerated, but the scarce severe effects may require intensive medical care. They may be classified as acute, subacute, and delayed. Their prevention and management are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>AcuteMost adverse events are mild, preventable and are related to the infusion of aa (with a very low incidence when using a master formula). The most frequent adverse events are nausea, headache, and abdominal disturbances. The most common biochemical alteration is hyperkalemia with an asymptomatic presentation. Patients with altered cardiac function may present congestive heart failure due to volume overload.In relation to the administration of the radiopharmaceutical, different adverse events may be presented, although they are more infrequent: <ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0105">-Carcinoide syndrome: This is the most frequent of the hormonal syndromes (1%–10% of treatments) and is the result of the secretion of different bioactive amines which may appear from the time of infusion up to 12−48 h later, especially during the first cycle. Carcinoid cardiopathy increases the severity of the clinical picture. It may manifest as hemodynamic instability, flushing, bronchospasm, cardiac arrythmias, diarrhea, metabolic acidosis, and alteration of consciousness<a class="elsevierStyleCrossRef" href="#bib0125">25</a>. The risk factors for developing a carcinoid crisis are: a history of a previous episode, elevated 5-HIAA and/or CgA levels, high tumoral load, mainly metastatic liver disease, carcinoid cardiopathy, advanced age and treatment with histamine release drugs. The determination of 5-HIAA in urine constitutes the most useful predictive biomarker in carcinoid syndrome.</li><li class="elsevierStyleListItem" id="lsti0110">-Catecholaminergic crisis: in general, the appearance of this crisis is not frequent and has mainly been described in patients with PG and PCC, tumors larger than 3 cm, uncontrolled pressure values and previous elevation of catecholamines.</li><li class="elsevierStyleListItem" id="lsti0115">-Hair loss, asthenia, reduction of appetite: These adverse events are usually mild and transitory<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a>.</li><li class="elsevierStyleListItem" id="lsti0120">-Tumoral lysis syndrome: this is an infrequent complication which generally appears on the third day post-treatment and produces deterioration of renal function.</li><li class="elsevierStyleListItem" id="lsti0125">-Severe hypoglycemia.</li></ul>Subacute<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0130">-Hematologic toxicity: this appears at 4−8 weeks after treatment and the platelets are the most frequently affected. It is generally mild and transitory but may be severe in around 2%–3% of the cases. This toxicity has been described in cases of acute leukemia or myelodysplastic syndromes (less than 2% of the treatments) mainly in patients over the age of 70 years, previously treated with alkylating agents or radiotherapy or who have received multiple lines of previous therapies.</li></ul>Delayed<ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0135">-Nephrotoxicity: this is considered a rare event due to the routine use of aa formulas and is currently a very unusual complication. Nephrotoxicity is most often associated with patients with a history of obstruction of the renal tract, diabetes, arterial hypertension or with previous kidney damage.</li><li class="elsevierStyleListItem" id="lsti0140">-Hepatic toxicity and/or ascites: this most frequently occurs in patients with wide-spread liver metastases.</li><li class="elsevierStyleListItem" id="lsti0145">-Transitory alteration of fertility: this is secondary to involvement of the Sertoli cells and is also transitory in nature.</li></ul>RetreatmentFollowing a period of response and/or disease stabilization, NET progress in most patients treated with PRRT. The efficacy and safety of retreatment with PRRT (R-PRRT) have been analyzed in studies with small patient cohorts, in NETs of different localizations and disease stages, and with a limited follow-up. These studies describe a great variability in the number of cycles, cumulative dose administered and, on occasions, alternate several radiopharmaceuticals (90Y and 177Lu) or their combinations<a class="elsevierStyleCrossRefs" href="#bib0140">28–32</a>.The largest cohort of patients from a single institution treated with R-PRRT-Lu was published by van der Zwan et al. and included 168 patients with NET of bronchial and GEP origin. The total mean cumulative retreatment doses administered (in the 168 patients) were 44.7 GBq and 59.7 GBq after re-treatment (13 patients). The patients receiving R-PRRT-Lu presented a significantly more prolonged OS than the patients in the control group. Those with mid-gut NET presented an OS of 77.3 months in comparison to 51 months in the control group, while patients with bronchial NET had an OS of 80.8 months versus 51.4 months in the controls, and lastly, the patients with pancreatic localization presented an OS of 93.9 months compared to 61.5 months in the control group. The authors concluded that R-PRRT-Lu may be safely and effectively performed with a cumulative dose administered of up to 60.5 GBq after progression to R-PRRT-Lu. The safety profile was similar to that of PRRT-Lu, the incidence of acute myeloid leukemia or myelodysplastic syndrome was not greater and renal toxicity grade III/IV was not observed.Two systematic reviews have recently been published which included both PRRT-Lu and PRRT-Y therapy. The first evaluated a total of 414 patients and reported a progression-free survival (PFS) of 12.52 months and an OS of 26.78 months<a class="elsevierStyleCrossRef" href="#bib0165">33</a>. The second review evaluated a total of 426 patients obtaining a PFS of 14.1 months and an OS of 26.8 months<a class="elsevierStyleCrossRef" href="#bib0170">34</a>. Both coincided in that salvage treatment is an effective therapeutic option with a safety profile similar to initial PRRT.There is still no consensus as to the ideal time to perform R-PRRT after progression, and long-term toxicities and their role in G2-G3 NET remain unknown.Retreatment with PRRT-Lu is indicated in patients with disease progression after objective response to the initial therapy and with a progression free time of 12–18 months, and is aimed at obtaining disease stability or regression, although the results are less favorable than with the initial treatment<a class="elsevierStyleCrossRef" href="#bib0175">35</a>.Key point:Retreatment with PRRT-Lu is indicated in patients with disease progression after objective response to initial therapy and with a progression free time of 12–18 months, and is aimed at obtaining disease stability or regression, although the results are less favorable than with the initial treatment.ResultsThe use of PRRT has demonstrated good results in terms of tumoral response, increase in PFS and improved quality of life with a good safety profile.Different phase I and II clinical trials have demonstrated the greater efficacy and tolerability of PRRT-Lu versus its predecessors 90Y and 111In, allowing therapy, imaging, and dosimetry to be performed at the same time with more favorable tissue penetrance for small sized lesions and acceptable dosimetry to limiting organs (bone marrow and kidney)<a class="elsevierStyleCrossRefs" href="#bib0180">36,37</a>.GEP-NET are probably the tumors most frequently studied with PRRT-Lu. In 2008, a study including 310 patients showed completed response (CR) and partial response (PR) in 2% and 28% of the cases, respectively, with an OS of 46 months after treatment and a PFS of 40 months. In a meta-analysis of 473 patients with GEP-NET carried out in 2015 a disease control rate of around 81%–82% was observed<a class="elsevierStyleCrossRef" href="#bib0190">38</a>.More recently, the NETTER-1 trial published in 2017 was the first randomized, multicenter phase III trial, and it demonstrated the efficacy and safety of [177Lu]Lu-DOTA-TATE versus treatment with high doses of octreotide LAR (60 mg/4 weeks) in patients with metastatic and inoperable mid-gut NET. The PFS was 30 months versus 8 months with octreotide, with an improvement in the activity and the quality of life in addition to controlling tumoral growth. There was a 79% reduction in the risk of progression or death compared with high-dose octreotide opening the door to authorization by the European Medicines Agency and the Food and Drug Administration and its inclusion in the principal therapeutic guidelines and extension of its use to pancreatic NET<a class="elsevierStyleCrossRef" href="#bib0195">39</a>.In NET of pulmonary origin, most publications are of retrospective series or small groups included in large series of GEP-NET. Nonetheless, PRRT has also demonstrated its efficacy in this localization. In a series of 23 patients with bronchial NET (included in a heterogeneous group together with other GEP-NET and of unknown origin), a specific PFS of 20 months and OS of 52 months was described<a class="elsevierStyleCrossRef" href="#bib0200">40</a>.A retrospective study published in 2020 including 25 patients with typical or atypical bronchial NET treated with PRRT-Lu or PRRT-Y, many of whom were on their third or fourth line, showed a PFS of 17 months and an OS of 42 months<a class="elsevierStyleCrossRef" href="#bib0205">41</a>.PRRT has also shown to be useful in PG and PCC as an alternative to [131I]MIBG, although in patients who are candidates to both therapies there continues to be controversy as to which to administer. In a retrospective study of 30 patients (27 PG and 3 PCC) treated with 4 cycles of 7.4 Gbq, the PFS was 91 months in parasympathetic PG with worse results in sympathetic PG and PCC. In a meta-analysis of patients with advanced disease treated with PRRT-Y and PRRT-Lu published in 2019, a rate of response of 25% was observed in the patients with a disease control rate of 84% and minimum adverse effects<a class="elsevierStyleCrossRefs" href="#bib0210">42,43</a>.Future perspectivesThere are several lines of investigation to improve the rate of objective response and survival with PRRT:New radionuclidesThe α-emitting radionuclides provide a significantly greater transfer of linear energy than the β-emitters, increasing the number of ruptures of the DNA chains and producing greater cell death with less collateral damage to healthy tissue. The α-emitters currently under study are bismuth-213 (213Bi), actinium-225 (225Ac) and lead-212 (212Pb), but the literature is scarce, and clinical trials are needed to evaluate the toxicity and efficacy limited by dose<a class="elsevierStyleCrossRef" href="#bib0220">44</a>.In the case of 213Bi, long-term response to treatment has been observed in humans with moderate chronic renal toxicity and less pronounced acute hematologic toxicity than in β-emitter therapies<a class="elsevierStyleCrossRef" href="#bib0225">45</a>. A phase I study with ²¹²Pb-DOTAMTATE has recently been completed and the results are pending publication<a class="elsevierStyleCrossRef" href="#bib0230">46</a>.Somatostatin antagonistsThe theory that internalization of the receptor is fundamental for greater tumoral uptake is the reason why only somatostatin agonists have been used up to now. However, studies in preclinical models have demonstrated significantly greater tumoral uptake with somatostatin antagonists as well as a longer survival and greater control of the tumor<a class="elsevierStyleCrossRefs" href="#bib0235">47,48</a>.The first pilot study with antagonists in human was performed with [177Lu]-DOTA-JR11, which showed promising results with a tumoral dose 1.7–10.6 times greater than with the agonist [177Lu]Lu-DOTA-TATE<a class="elsevierStyleCrossRef" href="#bib0245">49</a>. With this molecule an interventionist study has been carried out evaluating the experimental images with [68Ga]-DOTA-JR11 and treatment with [177Lu]-DOTA-JR11, and the results are pending<a class="elsevierStyleCrossRef" href="#bib0250">50</a>.The main concern of the use of these somatostatin antagonists is the risk of an increase of uptake in the bone marrow or the kidneys which would increase their toxicity.Other work lines<ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0150">-PRRT-Y in neoadjuvant treatment: this treatment has been described in a small series of patients to reduce tumor size and transform a tumor that was initially at the limit of resectability into one that is operable, using a dose of 7.4 GBq/m2 in 4–5 cycles every 6–9 weeks and achieving the objective in one third of the patients<a class="elsevierStyleCrossRef" href="#bib0255">51</a>.</li><li class="elsevierStyleListItem" id="lsti0155">-Arterial intrahepatic administration: the administration of [177Lu]Lu-DOTA-TATE through the hepatic artery has been considered in patients with predominantly hepatic disease. This route of administration can reduce the secondary effects by decreasing the quantity of radiopharmaceutical circulating systemically and increasing the concentration of radioactive activity in the hepatic lesions compared to conventional intravenous administration<a class="elsevierStyleCrossRef" href="#bib0260">52</a>.</li><li class="elsevierStyleListItem" id="lsti0160">-Chemo-PRRT: this has been described in a series of 38 patients in combination with different radiosensitizing agents such as capecitabin and temozolomide, together with PRRT-Lu therapy. It has been applied in NET with dual avidity for the radiotracers (18F-FDG and [68Ga]Ga-DOTA-TOC) with good hematological and renal tolerance<a class="elsevierStyleCrossRef" href="#bib0265">53</a>.</li></ul>In addition, at present, studies are being carried out to evaluate the efficacy or sequencing of PRRT versus other therapeutic agents. In the NCT03049189 phase III trial, which is currently recruiting patients, the efficacy of PRRT-Lu is being compared to everolimus in GEP-NET. The NCT04893785 trial is comparing the combination of cabozantinib and temozolamide in GEP- and pulmonary NET in progression with everolimus, sunitinib or PRRT. The NCT04919226 trial, which is pending the initiation of recruitment, aims to study the efficacy of PRRT in G2 – G3 GEP-NET versus treatments of reference (everolimus, capecitabine-temozolamide or the oxaliplatin fluorouracil and folinic acid scheme).<ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0165">-Selective internal PRRT-therapy (SIRT): the combination of PRRT and radioembolization with 90Y spheres was considered as an effective alternative in patients with NET with extrahepatic involvement and voluminous hepatic tumoral load since PRRT has lower objective response in large sized lesions. In a review of cases with 44 patients who initially received PRRT-Y or PRRT-Lu and afterwards SIRT with 90Y spheres, RECIST criteria indicated objective response of 16% with a disease control rate of 91%, considering the combination of these two therapies as safe<a class="elsevierStyleCrossRef" href="#bib0270">54</a>. A phase II trial with the combination of 4 cycles of PRRT and after 20 weeks radioembolization with 166Ho particles was also performed in 31 patients with G1-2 NET, showing PR at a hepatic level in 47% of the cases and stable disease in 37%. Long-term hepatotoxicity with the combination of this type of therapies remains under debate and requires long-term control studies<a class="elsevierStyleCrossRef" href="#bib0275">55</a>.</li></ul>Key point:PRRT with [177Lu]Lu-DOTA-TATE is a good therapeutic strategy in inoperable and metastatic NET, increasing the PFS and improving the quality of life. This treatment is well tolerated, safe, and with acute, generally mild, and self-limiting secondary effects.ConclusionThe inclusion of PRRT with [177Lu]Lu-DOTA-TATE is a good therapeutic strategy in patients with metastatic and inoperable NET, increasing the PFS and improving the quality of life. This treatment is well tolerated, safe and with acute, generally mild, and self-limiting secondary effects.The clinical presentation, morphology and biological behavior of NET are very heterogeneous, being difficult to diagnose and treat, and therefore, it is important to carry out a multidisciplinary approach. In this field, Nuclear Medicine fulfills a significant diagnostic and therapeutic task, being included in the guidelines within the therapeutic algorithms.Conflict of interestsThe authors declare no conflict of interests." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres1640381" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1462593" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1640382" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1462594" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction to neuroendocrine tumors and the concept or teragnosis" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Functional imaging studies in the theragnosis of neuroendocrine tumors" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Radiopharmaceuticals that detect the expression of somatostatin receptors" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "[F]fluorodeoxyglucose PET/CT" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "[I]Metaiodobenzylguanidine scintigraphy-SPECT/CT" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Therapy with peptides radiolabeled with [Lu]Lu-DOTA-TATE" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Objective, indications, and patient selection" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Mechanism of action" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Selection of patients who are candidates to therapy" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Contraindications to treatment" ] 4 => array:2 [ "identificador" => "sec0055" "titulo" => "Special situations" ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "Patient preparation, activity, and protocol of administration" ] 6 => array:2 [ "identificador" => "sec0065" "titulo" => "Criteria of discharge and treatment control" ] ] ] 7 => array:3 [ "identificador" => "sec0070" "titulo" => "Follow-up and evaluation of response" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0075" "titulo" => "Analytical follow-up and tumoral biomarkers" ] 1 => array:2 [ "identificador" => "sec0080" "titulo" => "Follow-up by imaging" ] ] ] 8 => array:3 [ "identificador" => "sec0085" "titulo" => "Adverse events" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0090" "titulo" => "Acute" ] 1 => array:2 [ "identificador" => "sec0095" "titulo" => "Subacute" ] 2 => array:2 [ "identificador" => "sec0100" "titulo" => "Delayed" ] ] ] 9 => array:2 [ "identificador" => "sec0105" "titulo" => "Retreatment" ] 10 => array:2 [ "identificador" => "sec0110" "titulo" => "Results" ] 11 => array:3 [ "identificador" => "sec0115" "titulo" => "Future perspectives" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0120" "titulo" => "New radionuclides" ] 1 => array:2 [ "identificador" => "sec0125" "titulo" => "Somatostatin antagonists" ] 2 => array:2 [ "identificador" => "sec0130" "titulo" => "Other work lines" ] ] ] 12 => array:2 [ "identificador" => "sec0135" "titulo" => "Conclusion" ] 13 => array:2 [ "identificador" => "sec0140" "titulo" => "Conflict of interests" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-10-07" "fechaAceptado" => "2021-11-10" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1462593" "palabras" => array:5 [ 0 => "[177Lu]Lu-DOTA-TATE" 1 => "PRRT" 2 => "Teragnosis" 3 => "Neuroendocrine tumor" 4 => "Radionuclide therapy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1462594" "palabras" => array:5 [ 0 => "[177Lu]Lu-DOTA-TATE" 1 => "PRRT" 2 => "Teragnosis" 3 => "Tumor neuroendocrino" 4 => "Terapia con radionúclidos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "This continuing education aims to present in a clear and easy-to-understand way, the biology of neuroendocrine tumors (NETs), the characteristics of somatostatin receptors, the selection of patients for radiolabelled peptide therapy (PRRT), the inclusion criteria to benefit from treatment with the minimum possible adverse effects, the administration protocol, follow-up and response evaluation. The functional imaging studies necessary to explore the biology of the tumor and to individualize the treatment are also carried out, and constitute the cornerstone for the development of teragnosis.Clinical trials are being developed to better define the position of PRRT within the broad therapeutic options, and among the future perspectives, there are several lines of research to improve the objective response rate and survival with PRRT, focused on the development of new agonists and somatostatin receptor antagonists, new radionuclides and radiosensitizing combination therapies.In conclusion, PRRT is a great therapeutic, well-tolerated and safe tool with generally mild and self-limited acute side effects, that must be sequenced at the best moment of the evolution of the disease of patients with NET. Candidate patients for PRRT should always be evaluated by a multidisciplinary clinical committee." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Esta formación pretende presentar de forma clara y de fácil comprensión, la biología de los tumores neuroendocrinos (TNE), las características de los receptores de somatostatina, cómo debe realizarse la selección de pacientes candidatos a terapia con péptidos radiomarcados (PRRT), si el paciente cumple los criterios para beneficiarse del tratamiento, con los mínimos efectos adversos posibles, el protocolo de administración, seguimiento y evaluación de respuesta. También se desarrollan los estudios de imagen funcional necesarios para explorar la biología del tumor e individualizar el tratamiento, que constituyen la piedra angular para el desarrollo de la teragnosis.Se están desarrollando ensayos clínicos para definir mejor la posición de PRRT dentro del amplio panorama terapéutico, y entre las perspectivas de futuro hay varias líneas de investigación para mejorar la tasa de respuesta objetiva y la supervivencia con PRRT, centradas en el desarrollo de nuevos agonistas y antagonistas del receptor de somatostatina, nuevos radionúclidos y terapias combinadas radiosensibilizantes.En conclusión la PRRT es un tratamiento bien tolerado, seguro y con efectos secundarios agudos, generalmente leves y autolimitados, que constituye una gran herramienta terapéutica que debe secuenciarse en el mejor momento de la evolución de la enfermedad de los pacientes con TNE. Los pacientes candidatos a la PRRT deben ser valorados siempre por un comité clínico multidisciplinar." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Prado-Wohlwend S, Bernal-Vergara JC, Utrera-Costero A, Cañón-Sánchez JR, Agudelo-Cifuentes M, Bello-Arques P. Terapia con péptidos radiomarcados con [177Lu]Lu-DOTA-TATE. Rev Esp Med Nucl Imagen Mol. 2022;41:54–64." ] ] "multimedia" => array:7 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1233 "Ancho" => 2917 "Tamanyo" => 274897 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Scheme of the composition of the radiopharmaceutical used in the theragnosis of somatostatin receptors." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1761 "Ancho" => 2500 "Tamanyo" => 279049 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Mechanism of action of [177Lu]Lu-DOTA-TATE." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1825 "Ancho" => 2500 "Tamanyo" => 289830 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Scheme of the [177Lu]Lu-DOTA-TATE administration protocol." ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1129 "Ancho" => 1250 "Tamanyo" => 53566 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "A. Maximum intensity projection (MIP) of a [68Ga]Ga-DOTA-TOC PET/CT study in a patient with pancreatic NET with Ki-67 of 20%. Multiple and intense uptakes are observed in the pancreas, liver, supradiaphragmatic lymph nodes, abdominal implants, and bone lesions in relation to the overexpression of somatostatin receptors. B and C. Scan of distribution in anterior and posterior projection at 24 h after the administration of 7.4 GBq of [177Lu]Lu-DOTA-TATE. The uptake is concordant with all the lesions visualized in the [68Ga]Ga-DOTA-TOC PET/CT." ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "NET: neuroendocrine tumors, NEC: neuroendocrine carcinomas, MiNEN: mixed non-neuroendocrine - neuroendocrine neoplasias." "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Classification of gastroenteropancreatic NET \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Differentiation \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Histological grade \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mitotic rate (mitosis/2 mm2) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Ki-67 \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G1 NET \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Well differentiated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><3% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G2 NET \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Well differentiated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intermediate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2−20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3%−20% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G3 NET \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Well differentiated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>20% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Small-cell NEC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Poorly differentiated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>20% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Large cell NEC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Poorly differentiated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>20% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MiNEN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Well or poorly differentiated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Variable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Variable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Variable \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2794679.png" ] ] 1 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Classification pulmonary NET \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Morphology \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cytology \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mitosis \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Typical carcinoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Carcinoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atypical carcinoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Carcinoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2−10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Large cell NEC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neuroendocrine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Large cell (>20 μm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>10 (±70) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Microcytic carcinoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neuroendocrine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Small cell (<20 μm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>10 (±80) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2794682.png" ] ] ] ] "descripcion" => array:1 [ "en" => "2019 classification of the World Health Organization of gastroenteropancreatic neuroendocrine tumors and the 2015 classification of pulmonary neuroendocrine tumors." ] ] 5 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Krenning score \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Uptake \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SSTR-RADS \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Findings \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Absence \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign lesion by biopsy or imaging \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Very low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Soft tissue or atypical bone lesion of metastatic NET \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Slightly less than or equal to hepatic uptake \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Doubtful lesion of malignancy in soft tissue or bone (due to doubtful uptake, intense uptake in atypical localization or lesions suggestive of malignancy but without uptake). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Greater than hepatic uptake \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intense uptake in typical NET localization without findings in conventional imaging \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Greater than splenic uptake \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intense uptake in typical NET localization with findings in conventional imaging \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2794680.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Krenning scale of intensity and uptake and integrated SSTR-RADS evaluation. Those localized in the shaded region are candidates to PRRT for SSTR expression." ] ] 6 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0035" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Presentation \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Adverse event \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Follow-up and/or treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="17" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Acute</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nausea, headache, abdominal disturbances \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Use low osmolarity solution \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Consider antiemetic before and/or during infusion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Congestive heart failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Slow infusion of amino acids \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Electrolyte imbalance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Use low osmolarity solution \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Catecholaminergic crisis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Premedication: -Avoid corticosteroids -Ondansetron 4 mg orally -Consider adrenergic α and β blockade if high risk. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Catecholaminergic crisis: -Stop infusion of the radiopharmaceutical -Maintain volume with saline solution 0.9% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-If hypertension: captopril 50 mg orally \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Severe hypertension: nitroprusiate 0.5–3 mcg/kg/min; phentolamine 1 mg (if necessary, repeat bolus of 5 mg); Nicardipine 5 mg/h in continuous perfusion until control of blood pressure \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Hypertension + tachycardia: Labetalol: infusion 20 mg/IV in slow bolus (maximum 300 mg) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-If cardiac arrhythmia: lidocaine 50−100 IV; Esmolol 50−200 mcg/kg/min IV. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Consider intensive care unit \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Carcinoid crisis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Premedication (if high risk): -Dexamethasone 4−8 mg -Ondansetron 4 mg orally -Octreotide 100 mcg SC ó 50 mcg IV -AntiH1 (dexchlorpheniramine 5 mg IV in slow infusion) -AntiH2 (ranitidine 50 mg IV in slow infusion) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Carcinoid crisis: -Stop infusion of the radiopharmaceutical -Octreotide 100−500 mcg SC or IV, maintain 50−100 mcg/h -Hydrocortisone or methylprednisolone 1−2 mg/kg/IV in slow infusion -If hypotension: phenylephrine or vasopressin -if hypertension: adrenergic α and β blockade -Maintain volume: Infusion of saline solution 0.9% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Flushing, pruritus, facial or uvula edema: -Dexchlorpheniramine 5−10 mg IV slow infusion, maintain 5 mg/6 h -Ranitidine 50 mg IV slow infusion, maintain 50 mg/6−8 h. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diarrhea -Monitor electrolytes, renal function, hemostasis, and transaminases - Hydro-electrolytic correction \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bronchospasm -Avoid adrenergic β stimulus -Corticosteroids: Hydrocortisone, methylprednisolone, beclomethasone, or fluticasone. -Ipratropium bromide 50−60 mcg inhalation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tumoral lysis syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Specific treatment. Consider intensive care unit. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subacute \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hematologic toxicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Periodic control with hemogram \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Delayed</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nephrotoxicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Periodic control of renal function \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatic toxicity, ascites \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Diet low in salt \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Treatment with diuretics \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Paracentesis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Peritoneal-venous shunt \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Loss of hair, asthenia, reduction of appetite \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Transitory alteration of fertility \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Based on the patient, consider sperm banks prior to therapy \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2794681.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Types of adverse events of treatment with [177Lu]Lu-DOTA-TATE and their treatment." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:55 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. 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Peptide receptor radionuclide therapy with [177Lu]Lu-DOTA-TATE

Terapia con péptidos radiomarcados con [177Lu]Lu-DOTA-TATE

S. Prado-Wohlwend

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prado_ste@gva.es

Corresponding author.

, J.C. Bernal-Vergara, A. Utrera-Costero, J.R. Cañón-Sánchez, M. Agudelo-Cifuentes, P. Bello-Arques, on behalf of the Endocrinology Working Group of the SEMNIM

Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction to neuroendocrine tumors and the concept or teragnosis</span><p id="par0005" class="elsevierStylePara elsevierViewall">Neuroendocrine tumors &#40;NET&#41; are a group of epithelial neoplasms arising from neuroendocrine cells which&#44; during the embryonic stage&#44; are distributed through the neural crest&#44; the endocrine glands&#44; pancreatic islets&#44; and the diffuse endocrine system&#46; NET cells are structured in the form of glandular&#44; trabecular&#44; or solid nests and produce abundant neurosecreting granules expressed by immunohistochemical markers such as chromogranin A &#40;CgA&#41;&#44; synaptophysin and specific neuronal enolase&#46; Although they may originate in any localization&#44; the most common are gastroenteropancreatic &#40;GEP&#41; &#40;66&#37;&#41; and pulmonary &#40;31&#37;&#41;&#44; being less frequent on the skin&#44; in adrenal or thyroid glands and the urogenital tract&#46; These tumors are complex due to the heterogeneity of their clinical presentation&#44; the need to use multiple tests to obtain a diagnosis and the possibility of applying different systemic and targeted therapies requiring multidisciplinary teams for their diagnosis&#44; follow-up&#44; and personalized management&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">While these tumors are infrequent&#44; their incidence has increased&#44; being estimated as 6&#46;8 cases per 100&#44;000 inhabitants&#44; probably due to the advances in diagnostic techniques and the more generalized use of multimodal imaging<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a>&#46; NET can be classified based on their histological and immunohistochemical characteristics&#46; The World Health Organization divides GEP-NET according to their proliferation index &#40;Ki-67&#41;&#44; mitotic rate and grade of cellular differentiation&#46; NET of pulmonary and thymus origin are classified in a similar way but without using the Ki-67 index<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Mixed neoplasias correspond to tumors with a non-endocrine and a neuroendocrine component that is generally neuroendocrine cancer&#46; These must be genotypically related tumors and the neuroendocrine component must correspond to at least 30&#37; of the tumor&#46; Whenever possible&#44; each component should be classified separately&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Paragangliomas &#40;PG&#41; and pheochromocytomas &#40;PCC&#41; are less common types of NET with an annual incidence of 1&#47;300&#44;000&#46; The PG originate in the autonomous extra-adrenal paraganglia&#44; and PCC are from the adrenal medulla&#46; The paraganglia are small organs mainly made up of neuroendocrine cells derived from the embryonic neural crest and together with PCC can secrete catecholamines and produce hormonal syndromes&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Another way to classify NET is as functioning and non-functioning tumors&#44; based on the presence or not of a clinical syndrome produced by hormone secretion&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Most pancreatic NET are non-functioning&#44; and in the small percentage of functioning tumors the secretion varies based on the pancreatic islet cells from which it is derived and may include gastrinomas&#44; insulinomas&#44; glucagonomas&#44; VIpomas or somatostatinomas&#46; NET of intestinal origin may also be functioning tumors producing a carcinoid syndrome mainly due to the secretion of serotonin<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Despite their heterogeneity in the tissue of origin&#44; NET share the expression of neuroendocrine immunohistochemical markers which facilitate the secretion of bioactive peptides such as CgA&#44; serotonin&#44; gastrin&#44; and insulin&#46; The release of these substances is regulated by somatostatin &#40;SS&#41;&#44; which is an oligopeptide that is produced endogenously&#44; mainly in the central nervous system&#46; This peptide interacts with the somatostatin transmembrane receptors &#40;SSTR&#41; of the cell surface&#44; which are present in more than 80&#37; of NET<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Up to five subtypes of SS receptors have been identified&#58; SSTR1&#44; SSTR2&#44; SSTR3&#44; SSTR4 and SSTR5&#46; The expression of the SSTR may vary among the different NET&#44; having a wide distribution in the different tissues and presenting several subtypes in the same tumor&#46; However&#44; SSTR2 followed by SSTR5 are the most frequently associated with NET&#46; Overexpression of these receptors&#44; especially SSTR2&#44; regarding healthy tissue is the cornerstone for the development of the theragnosis in these tumors<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;9</span></a>&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The concept of theragnosis refers to the possibility of using molecules with specific affinity for determined tumors for both their diagnosis and treatment&#46; It is a developing field that allows&#44; accurate personalized oncological treatment&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Among the theragnostic radiopharmaceuticals used in NET&#44; those using SSTR as a target stand out&#46; They are made up of three parts&#58; a radioactive metal &#40;<span class="elsevierStyleSup">68</span>Ga&#44; <span class="elsevierStyleSup">111</span>In and <span class="elsevierStyleSup">99m</span>Tc for diagnosis and <span class="elsevierStyleSup">177</span>Lu or <span class="elsevierStyleSup">90</span>Y for treatment&#41;&#44; a peptide analog with affinity for the membrane SSTR &#40;TOC&#44; TATE and NOC&#41; and a chelator that both binds and stabilizes the radioactive metal to avoid their dissociation <span class="elsevierStyleItalic">in vivo</span> &#40;DOTA and DPTA&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">The treatment of NET with radioisotopes is also called peptide receptor radionuclide therapy &#40;PRRT&#41; and can be performed with two radiopharmaceuticals&#58; &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE &#40;PRRT-Lu&#41; and &#91;<span class="elsevierStyleSup">90</span>Y&#93;Y-DOTA-TOC &#40;PRRT-Y&#41;&#46; We will focus on the first since it is the only one for which we have authorization&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Key point&#58;</span><span class="elsevierStyleItalic">The concept of theragnosis refers to the possibility of using molecules with specific affinity for determined tumors for both their diagnosis and treatment</span>&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Functional imaging studies in the theragnosis of neuroendocrine tumors</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Radiopharmaceuticals that detect the expression of somatostatin receptors</span><p id="par0065" class="elsevierStylePara elsevierViewall">The intense overexpression of SSTR in the cellular membrane of a large number of NET constitutes the basis of the use of functional imaging studies for their diagnosis&#46; Confirmation of this overexpression is essential to consider PRRT<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Functional imaging studies of SSTR may include&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0075" class="elsevierStylePara elsevierViewall">Scintigraphy and single photon emission computed tomography&#47;computerized tomography &#40;SPECT&#47;CT&#41; of SSTR &#40;SPECT&#47;CT-SSTR&#41; such as &#91;<span class="elsevierStyleSup">111</span>In&#93;octreotide &#40;OctreoScan&#174;&#41; and &#91;<span class="elsevierStyleSup">99m</span>Tc&#93;Tc-HYNIC-TOC &#40;Tektrotyd&#174;&#41;&#46; For years these techniques have been considered the gold standard of functional imaging despite having certain limitations with respect to the new positron emission tomography &#40;PET&#41;&#47;CT as well as lesser sensitivity due to their lower spatial resolution&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0080" class="elsevierStylePara elsevierViewall">PET&#47;CT-SSTR with &#91;<span class="elsevierStyleSup">68</span>Ga&#93;-DOTA-TOC&#47;TATE&#47;NOC&#46;</p></li></ul></p><p id="par0085" class="elsevierStylePara elsevierViewall">PET&#47;CT-SSTR studies require a shorter waiting and acquisition time&#44; reduce the dosimetry of the patient&#44; allow quantification of uptake&#44; and by being performed earlier&#44; present less biliary elimination<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#46; The TOC and TATE analogs show a high affinity for SSTR2 and SSTR5&#44; while NOC has less affinity for SSTR2 but has an additional binding to the SSTR3 and SSTR5&#46; The three labeled with <span class="elsevierStyleSup">68</span>Ga are currently widely used in routine clinical practice<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a>&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The condition necessary to administer PRRT is confirmation of elevated SSTR expression in functional imaging studies&#46; To characterize the intensity of uptake in both scintigraphy SPECT&#47;CT studies and PET&#47;CT&#44; the qualitative Krenning scale is usually used with numerical values from 0 to 4&#46; This scale was initially described for planar scintigraphy of SSTR&#44; but it was later validated for PET&#47;CT-SSTR&#46; In PET&#47;CT-SSTR a significantly higher level of uptake has been observed in the Krenning scale than in planar imaging and SPECT&#47;CT&#44; especially in lesions of less than 2&#8239;cm&#46; The intensity of uptake in the functional SSTR images should be integrated with the diameter and the extension of the tumor to optimize the selection of candidates to PRRT<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#46; As in other tumors&#44; to do this a structured SSTR-RADS reporting system has been proposed and is applied in the theragnosis of NET&#46; In this report the intensity of uptake in the functional image of SSTR is correlated with the localization &#40;typical or atypical&#41;&#44; the findings of the conventional images and the presence or not of a previous biopsy&#46; Patients with a Krenning score greater than or equal to 3 and SSTR-RADS greater than or equal to 4 are candidates for PRRT<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">&#91;<span class="elsevierStyleSup">18</span>F&#93;fluorodeoxyglucose PET&#47;CT</span><p id="par0095" class="elsevierStylePara elsevierViewall">PET&#47;CT-SSTR should not be the only functional image to evaluate in NET&#46; PET&#47;CT-SSTR and PET&#47;CT with &#91;<span class="elsevierStyleSup">18</span>F&#93;fluorodeoxyglucose &#40;<span class="elsevierStyleSup">18</span>F-FDG&#41; should be carried out as an integrated strategy in NET which are not of low grade &#40;G1&#41;&#46; In general&#44; the uptake of PET&#47;CT-SSTR is greater in low-grade NET &#40;G1 and G2&#41;&#44; while the avidity for a metabolic tracer such as <span class="elsevierStyleSup">18</span>F-FDG is higher in G2 and G3 NET&#46; <span class="elsevierStyleSup">18</span>F-FDG-PET&#47;CT allows evaluation of the state of dedifferentiation and the prognosis&#46; The combination of the avidity of <span class="elsevierStyleSup">18</span>F-FDG-PET&#47;CT and the lack of avidity in PET&#47;CT-SSRT may indicate the presence of a more aggressive&#44; high-grade NET that is not a candidate for PRRT and has a worse prognosis&#46; To the contrary&#44; a PET&#47;CT-SSTR with avidity in all the known lesions with <span class="elsevierStyleSup">18</span>F-FDG uptake likely corresponds to low-grade disease&#44; with a more indolent course&#44; better prognosis&#44; and candidate to PRRT&#46; In addition&#44; there may be significant tumoral heterogeneity in the same patient&#44; with the coexistence of well differentiated and poorly differentiated lesions<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">&#91;<span class="elsevierStyleSup">123</span>I&#93;Metaiodobenzylguanidine scintigraphy-SPECT&#47;CT</span><p id="par0100" class="elsevierStylePara elsevierViewall">This is an imaging study with theragnostic implications in PCC and PG &#40;and to a lesser&#44; extent medullary thyroid cancer&#41;&#46; It is not used to plan PRRT but rather to determine the expression of norepinephrine transporters &#40;NT&#41; and evaluate the alternative therapeutic option with &#91;<span class="elsevierStyleSup">131</span>I&#93;Metaiodobenzylguanidine &#40;MIBG&#41;&#46; In these patients both SSTR and NT expression should be assessed to select the best therapeutic target&#46; If greater or equal avidity of the lesions is observed by &#91;<span class="elsevierStyleSup">123</span>I&#93;MIBG than by SSTR&#44; &#91;<span class="elsevierStyleSup">131</span>I&#93;MIBG should be administered&#46; If the avidity is greater by the SSTR&#44; the choice should be PRRT<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Key point&#58;</span><span class="elsevierStyleItalic">PET&#47;CT-SSTR and <span class="elsevierStyleSup">18</span>F-FDG-PET&#47;CT should be carried out as an integrated imaging strategy in NET which are not low-grade&#46; In general&#44; the uptake of PET&#47;CT-SSTR is greater in low-grade NET &#40;G1 and G2&#41;&#44; while the avidity for a metabolic radiotracer such as <span class="elsevierStyleSup">18</span>F-FDG is higher in G2 and G3 NET</span>&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Therapy with peptides radiolabeled with &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE</span><p id="par0110" class="elsevierStylePara elsevierViewall">First line pharmacological treatment in well differentiated metastatic or inoperable NET that express SSTR involves somatostatin analogs &#40;SSA&#41;&#46; These analogs reduce the symptomatology derived from hormone hypersecretion and also have an antiproliferative effect&#46; When the disease progresses&#44; other systemic therapies are available for SSA&#44; such as everolimus&#44; sunitinib&#44; cytotoxic chemotherapy and PRRT&#46; Among these&#44; PRRT-Lu allows the selective administration of high doses of radiation to the tissues that overexpress SSTR with minimal systemic toxicity<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#46;</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Objective&#44; indications&#44; and patient selection</span><p id="par0115" class="elsevierStylePara elsevierViewall">Although the ideal objective would be complete disease remission&#44; the real objectives of PRRT are&#58; to stabilize the disease&#44; reduce local and secretory symptoms&#44; and improve the quality of life of the patients&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">In Spain&#44; &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE &#40;Lutathera&#174;&#41; was authorized by the Spanish Agency of Medications and Medical Devices &#40;AEMPS&#41; for PRRT in January 2018&#46; It is indicated in patients with metastatic or inoperable GEP-NET with overexpression of SSTR and well differentiated &#40;G1 and G2&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">All the patients who are candidates for this therapy should be evaluated by an expert multidisciplinary clinical committee to determine whether the patient fulfills the criteria for this treatment with the least adverse effects possible&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Key point&#58;</span><span class="elsevierStyleItalic">In Spain&#44; the indication for PRRT with con &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE authorized by AEMPS is for metastatic or inoperable GEP-NET with overexpression of SSTR and well differentiated &#40;grade 1 and 2&#41;&#46; The decision of administration should always be made by a multidisciplinary committee with expertise in NET&#44; and this is especially important is patients who may be more sensitive to its adverse effects</span>&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Mechanism of action</span><p id="par0135" class="elsevierStylePara elsevierViewall">The radiopharmaceutical &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE is formed by a semisynthetic SSA that has high affinity for SSTR2&#46; It binds to a &#946;-emitter radioactive isotope &#40;<span class="elsevierStyleSup">177</span>Lu&#41; with an energy of 0&#46;497&#8239;MeV&#44; range of 20 cells in diameter&#44; maximum tissue penetration of 2&#46;2&#8239;mm &#40;mean 0&#46;67&#8239;mm&#41; and a semidecay time of 6&#46;647 days&#46; In addition&#44; it is associated with an emission of &#947; radiation of 113&#8239;keV and 208&#8239;keV&#44; which allows acquiring scintigraphy and SPECT&#47;CT images post-treatment&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">&#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE binds to the SSTR2 that are overexpressed in NET&#44; is internalized and remained trapped in the lysosomes&#46; Its radiation produces cell death by rupture of the DNA chains&#46; It is scarcely metabolized and is mainly excreted in the urine &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Selection of patients who are candidates to therapy</span><p id="par0145" class="elsevierStylePara elsevierViewall">Candidate patients are those with metastatic or inoperable NET in progression to SSA&#44; with a Karnofsky scale &#62;60&#37; or Eastern Cooperative Oncology Group score &#60;2 and who fulfill the following characteristics&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0150" class="elsevierStylePara elsevierViewall">PET&#47;CT-SSTR or SPECT&#47;CT-SSTR&#58;</p></li></ul></p><p id="par0155" class="elsevierStylePara elsevierViewall">Overexpression of somatostatin receptors in lesions with an intensity of uptake &#8805;3 in the Krenning scale &#40;greater than the liver&#41;&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Tumors with a lower intensity of uptake &#40;Krenning 1 and 2&#41;&#44; or who present greater avidity for <span class="elsevierStyleSup">18</span>F-FDG than for SSTR imaging are not good candidates for treatment<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&#46; <ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0165" class="elsevierStylePara elsevierViewall">Analytical requirements&#58;</p></li></ul></p><p id="par0170" class="elsevierStylePara elsevierViewall">Hemoglobin &#62;8&#8239;g&#47;dL&#44; red blood cells &#62; 3000&#47;&#956;L&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Leucocytes &#62;3000&#47;&#956;L&#44; neutrophils &#62;1000&#47;&#956;L&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Platelets &#62;75&#8239;&#215;&#8239;10&#94;3&#47;&#181;L&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Bilirubin &#60;3 times the high limit of normality&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Serum albumin &#62;30&#8239;g&#47;L&#46; If albumin values are &#60;30&#8239;g&#47;L&#44; the prothrombin time must be normal&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Glomerular filtration rate &#40;GFR&#41; &#62;50&#8239;mL&#47;min&#46; The radiopharmaceutical can be administered in patients on dialysis&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Contraindications to treatment</span><p id="par0200" class="elsevierStylePara elsevierViewall">Absolute&#58; pregnancy&#44; myelosuppression&#44; and life expectancy less than 6 months&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Relative&#58; breast feeding&#44; renal insufficiency&#44; hematological toxicity without myelosuppression&#44; patients less than 18 years of age and carcinoid cardiopathy&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Special situations</span><p id="par0210" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0215" class="elsevierStylePara elsevierViewall">Renal insufficiency&#58; PRRT-Lu has shown to be safe in patients with renal insufficiency&#46; Precaution is recommended in patients on hemodialysis or with severe renal insufficiency &#40;GFR&#8239;&#60;&#8239;30&#41;&#44; in whom a reduction in the activity administered may be an option&#46; It is recommended to treat cases of hydronephrosis prior to undergoing PRRT<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0220" class="elsevierStylePara elsevierViewall">Previous chemotherapy&#58; there is insufficient evidence regarding the increase of risk of myelodysplasia and acute leukemia with PRRT in patients who have previously undergone cytotoxic chemotherapy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0225" class="elsevierStylePara elsevierViewall">Peritoneal and mesenteric carcinomatosis&#58; it is recommended to evaluate the administration of corticosteroids to prevent local inflammation and even intestinal obstruction&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0230" class="elsevierStylePara elsevierViewall">Pediatric age&#58; it may be useful&#44; especially in cases of PG and PCC&#46;</p></li></ul></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Patient preparation&#44; activity&#44; and protocol of administration</span><p id="par0235" class="elsevierStylePara elsevierViewall">Previous medical consultation with a nuclear medicine physician is recommended to explain the procedure&#44; the characteristics of the treatment&#44; the measures of radiological protection and to sign the informed consent&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Treatments which may diminish the uptake of &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE must be withdrawn&#58;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0245" class="elsevierStylePara elsevierViewall">SSA&#58; 4&#8211;6 weeks if of prolonged action and at least 24&#8239;h for those of short action&#46; They may be reinitiated 4&#8211;24&#8239;h after each treatment cycle&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">-</span><p id="par0250" class="elsevierStylePara elsevierViewall">Chemotherapy&#44; interferon&#44; antiangiogenics&#58; 4&#8211;6 weeks&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">-</span><p id="par0255" class="elsevierStylePara elsevierViewall">Everolimus&#58; 10 days before&#46;</p></li></ul></p><p id="par0260" class="elsevierStylePara elsevierViewall">A total of 4 treatment cycles are administered&#44; separated by 8&#8211;10 weeks&#44; with a recommended dose of 7&#46;4&#8239;GBq &#40;200&#8239;mCi&#41;&#46; In patients with hematological toxicity&#44; the use of half the dose is recommended &#40;3&#46;7&#8239;GBq&#41;&#46; If this resolves in the following 16 weeks&#44; the treatment may be continued with the standard activity&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Although there may be small differences among the centers performing this therapy&#44; an example of the administration protocol is described below&#58;</p><p id="par0270" class="elsevierStylePara elsevierViewall">The patient is admitted to the metabolic therapy unit&#59; the weight&#44; height and vital signs are registered&#59; the venous access is prepared&#44; and the protocol is initiated &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">-</span><p id="par0275" class="elsevierStylePara elsevierViewall">Minute 0&#58; premedication with antiemetics &#40;for example&#44; ondansetron 4&#8722;8&#8239;mg&#41; to prevent vomiting secondary to the metabolic acidosis produced by the administration of amino acids &#40;aa&#41; and may be maintained every 8&#8239;h during admission&#46; This effect is significantly reduced if a master formula composed of lysine and arginine is used instead of a commercial formula&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">-</span><p id="par0280" class="elsevierStylePara elsevierViewall">Minute 30&#58; begin the infusion of aa &#40;2&#46;5&#37; of lysine and 2&#46;5&#37; of arginine&#41; in 1&#8239;L of water for injection during a minimum of 4&#8239;h to prevent renal toxicity&#44; and for reabsorption of the radiopharmaceutical in the proximal convoluted tubule&#46; If the concentration indicated above is not available in the preparation center&#44; commercial preparations which best adjust to the desired arginine and lysine concentrations can be used&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">-</span><p id="par0285" class="elsevierStylePara elsevierViewall">Minute 60&#58; begin the administration of &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE&#44; 50&#8239;mL over 30&#8239;min&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">-</span><p id="par0290" class="elsevierStylePara elsevierViewall">Minute 90&#58; maintain the aa infusion until completing the total infusion time&#46; To minimize the dose of radiation to the bladder&#44; encourage hydration during the remainder of the admission&#46; In patients with carcinoid cardiopathy the infusion volume can be reduced&#44; and the length of infusion lengthened to avoid volume overload&#46;</p></li></ul></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Criteria of discharge and treatment control</span><p id="par0295" class="elsevierStylePara elsevierViewall">Approximately 50&#37; of the activity of &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE administered is eliminated by the urinary tract in the first 6&#8239;h&#46; Based on the calculations of radiation exposure using total body clearance and exposure rate to one meter in 24&#8239;h&#44; it has been described that patients may be treated on an outpatient basis<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#46; In some centers the patients remain admitted for 24&#8239;h follow-up&#44; control of vital signs&#44; rapid identification of adverse effects and acquisition of images of post-treatment distribution&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">Between 4 and 24&#8239;h after the administration of the radiopharmaceutical&#44; a whole body distribution scan &#40;medium energy collimator&#44; phototopic 113 and 208&#8239;keV&#41; is performed to evaluate the concordance of the uptakes of &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE with the tumoral lesions described in the SSTR diagnostic studies&#46; The 24&#8239;h image has less background activity and better quality&#44; which is more manifested in areas of physiological uptake such as the liver&#46; In the case of the presence of small sized liver involvement it is useful to obtain 24&#8239;h images and SPECT&#47;CT to improve the localization of the lesions&#46; In addition&#44; SPECT&#47;CT allows performing dosimetric studies &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Follow-up and evaluation of response</span><p id="par0305" class="elsevierStylePara elsevierViewall">The follow-up of these patients is focused on the clinical symptoms&#44; imaging techniques&#44; analytical findings and tumoral biomarkers&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">In general&#44; in GEP and pulmonary G1 and G2 NET an initial clinical follow-up of imaging and biomarkers is recommended every 3 months&#46; In confirmed stable disease or slow growth after 15 months&#44; imaging controls can be made every 6&#8211;12 months and clinical and biomarker controls every 3&#8211;6 months&#46; Patients with aggressive lesions or of rapid progression should continue with imaging controls every 3 months&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall">The frequency of controls should be increased in patients with risk factors such as high-grade tumors&#44; elevated tumoral load&#44; wide-spread disease&#44; aggressive behavior&#44; severe endocrine symptoms&#44; weight loss or clinical worsening and CgA levels more than 10-fold the normal values<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#46;</p><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Analytical follow-up and tumoral biomarkers</span><p id="par0320" class="elsevierStylePara elsevierViewall">The European Association of Nuclear Medicine guidelines recommend performing an analytical control at 2&#44; 4 and 6 weeks after every treatment including liver and renal function tests and hemogram to determine if it is adequate to continue with the administration of the next dose&#46; Once the fourth cycle has been completed&#44; the controls are made every 8&#8211;12 weeks during the first 12 months followed by twice a year thereafter&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">The following are among the tumoral biomarkers most frequently used in patient follow-up&#58;<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">-</span><p id="par0330" class="elsevierStylePara elsevierViewall">CgA&#58; most frequently used in G1 and G2&#46; This biomarker indicates changes in tumoral load and secretory activity&#46; It is a prognostic indicator in small intestine NET and of possible recurrences&#46; It may be elevated in the absence of disease &#40;IBPs proton pump inhibitor&#44; chronic gastritis&#44; renal insufficiency&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">-</span><p id="par0335" class="elsevierStylePara elsevierViewall">CgB&#58; for the follow-up of rectal and pulmonary NET&#46;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">-</span><p id="par0340" class="elsevierStylePara elsevierViewall">5-hydroxyindoleacetic acid &#40;5-HIAA&#41;&#58; in NET of the small intestine&#44; appendix&#44; and serotonin-producing pulmonary NET&#44; especially those with carcinoid syndrome&#46; It may be altered by some foods&#46;</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">-</span><p id="par0345" class="elsevierStylePara elsevierViewall">Gastrointestinal hormones&#58; in functioning pancreatic-duodenal NET the hormone produced is used as a biomarker&#44; although its prognostic value is not clear&#46;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">-</span><p id="par0350" class="elsevierStylePara elsevierViewall">Brain natriuretic peptide&#58; every one or two years in patients with carcinoid syndrome to detect the appearance of carcinoid cardiopathy&#46;</p></li></ul></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Follow-up by imaging</span><p id="par0355" class="elsevierStylePara elsevierViewall">Abdominopelvic thoracic CT with a 3-phase hepatic study is the preferred conventional imaging technique&#46; An abdominal magnetic resonance study may be considered in the follow-up of hepatic lesions and in young patients to reduce the radiation dose&#46; The functional imaging studies include performing SSTR studies &#40;SPECT&#47;CT-SSTR or PET&#47;CT-SSTR&#41; and in G2-G3 NET <span class="elsevierStyleSup">18</span>F-FDG-PET&#47;CT&#44; and both may be carried out based on the characteristics of the patient&#46;</p><p id="par0360" class="elsevierStylePara elsevierViewall">The evaluation of response to treatment is complex due to the particular characteristics of NET&#44; such as their high vascularization&#44; and the changes produced by targeted therapies such as PRRT&#46;</p><p id="par0365" class="elsevierStylePara elsevierViewall">The Response Evaluation Criteria in Solid Tumors &#40;RECIST&#41; criteria may be suboptimal because they do not show the cystic or necrotic changes produced within the tumor&#46; As an alternative&#44; the CHOI criteria have been considered&#44; which&#44; in addition to size&#44; introduce the attenuation of the tumor in Hounsfield Units &#40;HU&#41; and have shown better adjustment to overall survival &#40;OS&#41; in patients with response to PRRT compared to the RECIST criteria<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a>&#46; The PET Response Criteria in Solid Tumors &#40;PERCIST&#41; have not yet been standardized for evaluating the response of NET by PET&#47;CT-SSTR&#46; The main indications of molecular imaging in the follow-up of NET are the presence of a clinical-biochemical-morphological dissociation and consideration of PRRT with the aim of optimizing the imaging studies and radiation received by the patient&#46;</p><p id="par0370" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Key point&#58;</span><span class="elsevierStyleItalic">The RECIST criteria may be suboptimal because they do not demonstrate the cystic or necrotic changes produced within the tumor&#46; As an alternative&#44; the CHOI criteria have been considered&#44; which&#44; in addition to size&#44; introduce the attenuation of the tumor in HU and have shown better adjustment to overall survival in patients with response to PRRT compared to the RECIST criteria</span>&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Adverse events</span><p id="par0375" class="elsevierStylePara elsevierViewall">In general&#44; adverse events are mild&#44; self-limiting and well tolerated&#44; but the scarce severe effects may require intensive medical care&#46; They may be classified as acute&#44; subacute&#44; and delayed&#46; Their prevention and management are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Acute</span><p id="par0380" class="elsevierStylePara elsevierViewall">Most adverse events are mild&#44; preventable and are related to the infusion of aa &#40;with a very low incidence when using a master formula&#41;&#46; The most frequent adverse events are nausea&#44; headache&#44; and abdominal disturbances&#46; The most common biochemical alteration is hyperkalemia with an asymptomatic presentation&#46; Patients with altered cardiac function may present congestive heart failure due to volume overload&#46;</p><p id="par0385" class="elsevierStylePara elsevierViewall">In relation to the administration of the radiopharmaceutical&#44; different adverse events may be presented&#44; although they are more infrequent&#58; <ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">-</span><p id="par0390" class="elsevierStylePara elsevierViewall">Carcinoide syndrome&#58; This is the most frequent of the hormonal syndromes &#40;1&#37;&#8211;10&#37; of treatments&#41; and is the result of the secretion of different bioactive amines which may appear from the time of infusion up to 12&#8722;48&#8239;h later&#44; especially during the first cycle&#46; Carcinoid cardiopathy increases the severity of the clinical picture&#46; It may manifest as hemodynamic instability&#44; flushing&#44; bronchospasm&#44; cardiac arrythmias&#44; diarrhea&#44; metabolic acidosis&#44; and alteration of consciousness<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#46; The risk factors for developing a carcinoid crisis are&#58; a history of a previous episode&#44; elevated 5-HIAA and&#47;or CgA levels&#44; high tumoral load&#44; mainly metastatic liver disease&#44; carcinoid cardiopathy&#44; advanced age and treatment with histamine release drugs&#46; The determination of 5-HIAA in urine constitutes the most useful predictive biomarker in carcinoid syndrome&#46;</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">-</span><p id="par0395" class="elsevierStylePara elsevierViewall">Catecholaminergic crisis&#58; in general&#44; the appearance of this crisis is not frequent and has mainly been described in patients with PG and PCC&#44; tumors larger than 3&#8239;cm&#44; uncontrolled pressure values and previous elevation of catecholamines&#46;</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">-</span><p id="par0400" class="elsevierStylePara elsevierViewall">Hair loss&#44; asthenia&#44; reduction of appetite&#58; These adverse events are usually mild and transitory<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">-</span><p id="par0405" class="elsevierStylePara elsevierViewall">Tumoral lysis syndrome&#58; this is an infrequent complication which generally appears on the third day post-treatment and produces deterioration of renal function&#46;</p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">-</span><p id="par0410" class="elsevierStylePara elsevierViewall">Severe hypoglycemia&#46;</p></li></ul></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Subacute</span><p id="par0415" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">-</span><p id="par0420" class="elsevierStylePara elsevierViewall">Hematologic toxicity&#58; this appears at 4&#8722;8 weeks after treatment and the platelets are the most frequently affected&#46; It is generally mild and transitory but may be severe in around 2&#37;&#8211;3&#37; of the cases&#46; This toxicity has been described in cases of acute leukemia or myelodysplastic syndromes &#40;less than 2&#37; of the treatments&#41; mainly in patients over the age of 70 years&#44; previously treated with alkylating agents or radiotherapy or who have received multiple lines of previous therapies&#46;</p></li></ul></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Delayed</span><p id="par0425" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">-</span><p id="par0430" class="elsevierStylePara elsevierViewall">Nephrotoxicity&#58; this is considered a rare event due to the routine use of aa formulas and is currently a very unusual complication&#46; Nephrotoxicity is most often associated with patients with a history of obstruction of the renal tract&#44; diabetes&#44; arterial hypertension or with previous kidney damage&#46;</p></li><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">-</span><p id="par0435" class="elsevierStylePara elsevierViewall">Hepatic toxicity and&#47;or ascites&#58; this most frequently occurs in patients with wide-spread liver metastases&#46;</p></li><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">-</span><p id="par0440" class="elsevierStylePara elsevierViewall">Transitory alteration of fertility&#58; this is secondary to involvement of the Sertoli cells and is also transitory in nature&#46;</p></li></ul></p></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Retreatment</span><p id="par0445" class="elsevierStylePara elsevierViewall">Following a period of response and&#47;or disease stabilization&#44; NET progress in most patients treated with PRRT&#46; The efficacy and safety of retreatment with PRRT &#40;R-PRRT&#41; have been analyzed in studies with small patient cohorts&#44; in NETs of different localizations and disease stages&#44; and with a limited follow-up&#46; These studies describe a great variability in the number of cycles&#44; cumulative dose administered and&#44; on occasions&#44; alternate several radiopharmaceuticals &#40;<span class="elsevierStyleSup">90</span>Y and <span class="elsevierStyleSup">177</span>Lu&#41; or their combinations<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#8211;32</span></a>&#46;</p><p id="par0450" class="elsevierStylePara elsevierViewall">The largest cohort of patients from a single institution treated with R-PRRT-Lu was published by van der Zwan et al&#46; and included 168 patients with NET of bronchial and GEP origin&#46; The total mean cumulative retreatment doses administered &#40;in the 168 patients&#41; were 44&#46;7&#8239;GBq and 59&#46;7&#8239;GBq after re-treatment &#40;13 patients&#41;&#46; The patients receiving R-PRRT-Lu presented a significantly more prolonged OS than the patients in the control group&#46; Those with mid-gut NET presented an OS of 77&#46;3 months in comparison to 51 months in the control group&#44; while patients with bronchial NET had an OS of 80&#46;8 months versus 51&#46;4 months in the controls&#44; and lastly&#44; the patients with pancreatic localization presented an OS of 93&#46;9 months compared to 61&#46;5 months in the control group&#46; The authors concluded that R-PRRT-Lu may be safely and effectively performed with a cumulative dose administered of up to 60&#46;5&#8239;GBq after progression to R-PRRT-Lu&#46; The safety profile was similar to that of PRRT-Lu&#44; the incidence of acute myeloid leukemia or myelodysplastic syndrome was not greater and renal toxicity grade III&#47;IV was not observed&#46;</p><p id="par0455" class="elsevierStylePara elsevierViewall">Two systematic reviews have recently been published which included both PRRT-Lu and PRRT-Y therapy&#46; The first evaluated a total of 414 patients and reported a progression-free survival &#40;PFS&#41; of 12&#46;52 months and an OS of 26&#46;78 months<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&#46; The second review evaluated a total of 426 patients obtaining a PFS of 14&#46;1 months and an OS of 26&#46;8 months<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a>&#46; Both coincided in that salvage treatment is an effective therapeutic option with a safety profile similar to initial PRRT&#46;</p><p id="par0460" class="elsevierStylePara elsevierViewall">There is still no consensus as to the ideal time to perform R-PRRT after progression&#44; and long-term toxicities and their role in G2-G3 NET remain unknown&#46;</p><p id="par0465" class="elsevierStylePara elsevierViewall">Retreatment with PRRT-Lu is indicated in patients with disease progression after objective response to the initial therapy and with a progression free time of 12&#8211;18 months&#44; and is aimed at obtaining disease stability or regression&#44; although the results are less favorable than with the initial treatment<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&#46;</p><p id="par0470" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Key point&#58;</span><span class="elsevierStyleItalic">Retreatment with PRRT-Lu is indicated in patients with disease progression after objective response to initial therapy and with a progression free time of 12&#8211;18 months&#44; and is aimed at obtaining disease stability or regression&#44; although the results are less favorable than with the initial treatment</span>&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Results</span><p id="par0475" class="elsevierStylePara elsevierViewall">The use of PRRT has demonstrated good results in terms of tumoral response&#44; increase in PFS and improved quality of life with a good safety profile&#46;</p><p id="par0480" class="elsevierStylePara elsevierViewall">Different phase I and II clinical trials have demonstrated the greater efficacy and tolerability of PRRT-Lu versus its predecessors <span class="elsevierStyleSup">90</span>Y and <span class="elsevierStyleSup">111</span>In&#44; allowing therapy&#44; imaging&#44; and dosimetry to be performed at the same time with more favorable tissue penetrance for small sized lesions and acceptable dosimetry to limiting organs &#40;bone marrow and kidney&#41;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37</span></a>&#46;</p><p id="par0485" class="elsevierStylePara elsevierViewall">GEP-NET are probably the tumors most frequently studied with PRRT-Lu&#46; In 2008&#44; a study including 310 patients showed completed response &#40;CR&#41; and partial response &#40;PR&#41; in 2&#37; and 28&#37; of the cases&#44; respectively&#44; with an OS of 46 months after treatment and a PFS of 40 months&#46; In a meta-analysis of 473 patients with GEP-NET carried out in 2015 a disease control rate of around 81&#37;&#8211;82&#37; was observed<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#46;</p><p id="par0490" class="elsevierStylePara elsevierViewall">More recently&#44; the NETTER-1 trial published in 2017 was the first randomized&#44; multicenter phase III trial&#44; and it demonstrated the efficacy and safety of &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE versus treatment with high doses of octreotide LAR &#40;60&#8239;mg&#47;4 weeks&#41; in patients with metastatic and inoperable mid-gut NET&#46; The PFS was 30 months versus 8 months with octreotide&#44; with an improvement in the activity and the quality of life in addition to controlling tumoral growth&#46; There was a 79&#37; reduction in the risk of progression or death compared with high-dose octreotide opening the door to authorization by the European Medicines Agency and the Food and Drug Administration and its inclusion in the principal therapeutic guidelines and extension of its use to pancreatic NET<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a>&#46;</p><p id="par0495" class="elsevierStylePara elsevierViewall">In NET of pulmonary origin&#44; most publications are of retrospective series or small groups included in large series of GEP-NET&#46; Nonetheless&#44; PRRT has also demonstrated its efficacy in this localization&#46; In a series of 23 patients with bronchial NET &#40;included in a heterogeneous group together with other GEP-NET and of unknown origin&#41;&#44; a specific PFS of 20 months and OS of 52 months was described<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>&#46;</p><p id="par0500" class="elsevierStylePara elsevierViewall">A retrospective study published in 2020 including 25 patients with typical or atypical bronchial NET treated with PRRT-Lu or PRRT-Y&#44; many of whom were on their third or fourth line&#44; showed a PFS of 17 months and an OS of 42 months<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>&#46;</p><p id="par0505" class="elsevierStylePara elsevierViewall">PRRT has also shown to be useful in PG and PCC as an alternative to &#91;<span class="elsevierStyleSup">131</span>I&#93;MIBG&#44; although in patients who are candidates to both therapies there continues to be controversy as to which to administer&#46; In a retrospective study of 30 patients &#40;27&#8239;PG and 3 PCC&#41; treated with 4 cycles of 7&#46;4 Gbq&#44; the PFS was 91 months in parasympathetic PG with worse results in sympathetic PG and PCC&#46; In a meta-analysis of patients with advanced disease treated with PRRT-Y and PRRT-Lu published in 2019&#44; a rate of response of 25&#37; was observed in the patients with a disease control rate of 84&#37; and minimum adverse effects<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;43</span></a>&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Future perspectives</span><p id="par0510" class="elsevierStylePara elsevierViewall">There are several lines of investigation to improve the rate of objective response and survival with PRRT&#58;</p><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">New radionuclides</span><p id="par0515" class="elsevierStylePara elsevierViewall">The &#945;-emitting radionuclides provide a significantly greater transfer of linear energy than the &#946;-emitters&#44; increasing the number of ruptures of the DNA chains and producing greater cell death with less collateral damage to healthy tissue&#46; The &#945;-emitters currently under study are bismuth-213 &#40;<span class="elsevierStyleSup">213</span>Bi&#41;&#44; actinium-225 &#40;<span class="elsevierStyleSup">225</span>Ac&#41; and lead-212 &#40;<span class="elsevierStyleSup">212</span>Pb&#41;&#44; but the literature is scarce&#44; and clinical trials are needed to evaluate the toxicity and efficacy limited by dose<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a>&#46;</p><p id="par0520" class="elsevierStylePara elsevierViewall">In the case of <span class="elsevierStyleSup">213</span>Bi&#44; long-term response to treatment has been observed in humans with moderate chronic renal toxicity and less pronounced acute hematologic toxicity than in &#946;-emitter therapies<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a>&#46; A phase I study with &#178;&#185;&#178;Pb-DOTAMTATE has recently been completed and the results are pending publication<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a>&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Somatostatin antagonists</span><p id="par0525" class="elsevierStylePara elsevierViewall">The theory that internalization of the receptor is fundamental for greater tumoral uptake is the reason why only somatostatin agonists have been used up to now&#46; However&#44; studies in preclinical models have demonstrated significantly greater tumoral uptake with somatostatin antagonists as well as a longer survival and greater control of the tumor<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47&#44;48</span></a>&#46;</p><p id="par0530" class="elsevierStylePara elsevierViewall">The first pilot study with antagonists in human was performed with &#91;<span class="elsevierStyleSup">177</span>Lu&#93;-DOTA-JR11&#44; which showed promising results with a tumoral dose 1&#46;7&#8211;10&#46;6 times greater than with the agonist &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a>&#46; With this molecule an interventionist study has been carried out evaluating the experimental images with &#91;<span class="elsevierStyleSup">68</span>Ga&#93;-DOTA-JR11 and treatment with &#91;<span class="elsevierStyleSup">177</span>Lu&#93;-DOTA-JR11&#44; and the results are pending<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a>&#46;</p><p id="par0535" class="elsevierStylePara elsevierViewall">The main concern of the use of these somatostatin antagonists is the risk of an increase of uptake in the bone marrow or the kidneys which would increase their toxicity&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Other work lines</span><p id="par0540" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">-</span><p id="par0545" class="elsevierStylePara elsevierViewall">PRRT-Y in neoadjuvant treatment&#58; this treatment has been described in a small series of patients to reduce tumor size and transform a tumor that was initially at the limit of resectability into one that is operable&#44; using a dose of 7&#46;4&#8239;GBq&#47;m2 in 4&#8211;5 cycles every 6&#8211;9 weeks and achieving the objective in one third of the patients<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">-</span><p id="par0550" class="elsevierStylePara elsevierViewall">Arterial intrahepatic administration&#58; the administration of &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE through the hepatic artery has been considered in patients with predominantly hepatic disease&#46; This route of administration can reduce the secondary effects by decreasing the quantity of radiopharmaceutical circulating systemically and increasing the concentration of radioactive activity in the hepatic lesions compared to conventional intravenous administration<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">-</span><p id="par0555" class="elsevierStylePara elsevierViewall">Chemo-PRRT&#58; this has been described in a series of 38 patients in combination with different radiosensitizing agents such as capecitabin and temozolomide&#44; together with PRRT-Lu therapy&#46; It has been applied in NET with dual avidity for the radiotracers &#40;<span class="elsevierStyleSup">18</span>F-FDG and &#91;<span class="elsevierStyleSup">68</span>Ga&#93;Ga-DOTA-TOC&#41; with good hematological and renal tolerance<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a>&#46;</p></li></ul></p><p id="par0560" class="elsevierStylePara elsevierViewall">In addition&#44; at present&#44; studies are being carried out to evaluate the efficacy or sequencing of PRRT versus other therapeutic agents&#46; In the NCT03049189 phase III trial&#44; which is currently recruiting patients&#44; the efficacy of PRRT-Lu is being compared to everolimus in GEP-NET&#46; The NCT04893785 trial is comparing the combination of cabozantinib and temozolamide in GEP- and pulmonary NET in progression with everolimus&#44; sunitinib or PRRT&#46; The NCT04919226 trial&#44; which is pending the initiation of recruitment&#44; aims to study the efficacy of PRRT in G2 &#8211; G3 GEP-NET versus treatments of reference &#40;everolimus&#44; capecitabine-temozolamide or the oxaliplatin fluorouracil and folinic acid scheme&#41;&#46;<ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">-</span><p id="par0565" class="elsevierStylePara elsevierViewall">Selective internal PRRT-therapy &#40;SIRT&#41;&#58; the combination of PRRT and radioembolization with <span class="elsevierStyleSup">90</span>Y spheres was considered as an effective alternative in patients with NET with extrahepatic involvement and voluminous hepatic tumoral load since PRRT has lower objective response in large sized lesions&#46; In a review of cases with 44 patients who initially received PRRT-Y or PRRT-Lu and afterwards SIRT with <span class="elsevierStyleSup">90</span>Y spheres&#44; RECIST criteria indicated objective response of 16&#37; with a disease control rate of 91&#37;&#44; considering the combination of these two therapies as safe<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a>&#46; A phase II trial with the combination of 4 cycles of PRRT and after 20 weeks radioembolization with <span class="elsevierStyleSup">166</span>Ho particles was also performed in 31 patients with G1-2 NET&#44; showing PR at a hepatic level in 47&#37; of the cases and stable disease in 37&#37;&#46; Long-term hepatotoxicity with the combination of this type of therapies remains under debate and requires long-term control studies<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a>&#46;</p></li></ul></p></span></span><p id="par0580" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Key point&#58;</span><span class="elsevierStyleItalic">PRRT with &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE is a good therapeutic strategy in inoperable and metastatic NET&#44; increasing the PFS and improving the quality of life&#46; This treatment is well tolerated&#44; safe&#44; and with acute&#44; generally mild&#44; and self-limiting secondary effects</span>&#46;</p><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conclusion</span><p id="par0570" class="elsevierStylePara elsevierViewall">The inclusion of PRRT with &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE is a good therapeutic strategy in patients with metastatic and inoperable NET&#44; increasing the PFS and improving the quality of life&#46; This treatment is well tolerated&#44; safe and with acute&#44; generally mild&#44; and self-limiting secondary effects&#46;</p><p id="par0575" class="elsevierStylePara elsevierViewall">The clinical presentation&#44; morphology and biological behavior of NET are very heterogeneous&#44; being difficult to diagnose and treat&#44; and therefore&#44; it is important to carry out a multidisciplinary approach&#46; In this field&#44; Nuclear Medicine fulfills a significant diagnostic and therapeutic task&#44; being included in the guidelines within the therapeutic algorithms&#46;</p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conflict of interests</span><p id="par0585" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interests&#46;</p></span></span>"
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          "titulo" => "Introduction to neuroendocrine tumors and the concept or teragnosis"
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          "titulo" => "Therapy with peptides radiolabeled with &#91;Lu&#93;Lu-DOTA-TATE"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">This continuing education aims to present in a clear and easy-to-understand way&#44; the biology of neuroendocrine tumors &#40;NETs&#41;&#44; the characteristics of somatostatin receptors&#44; the selection of patients for radiolabelled peptide therapy &#40;PRRT&#41;&#44; the inclusion criteria to benefit from treatment with the minimum possible adverse effects&#44; the administration protocol&#44; follow-up and response evaluation&#46; The functional imaging studies necessary to explore the biology of the tumor and to individualize the treatment are also carried out&#44; and constitute the cornerstone for the development of teragnosis&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Clinical trials are being developed to better define the position of PRRT within the broad therapeutic options&#44; and among the future perspectives&#44; there are several lines of research to improve the objective response rate and survival with PRRT&#44; focused on the development of new agonists and somatostatin receptor antagonists&#44; new radionuclides and radiosensitizing combination therapies&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">In conclusion&#44; PRRT is a great therapeutic&#44; well-tolerated and safe tool with generally mild and self-limited acute side effects&#44; that must be sequenced at the best moment of the evolution of the disease of patients with NET&#46; Candidate patients for PRRT should always be evaluated by a multidisciplinary clinical committee&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Esta formaci&#243;n pretende presentar de forma clara y de f&#225;cil comprensi&#243;n&#44; la biolog&#237;a de los tumores neuroendocrinos &#40;TNE&#41;&#44; las caracter&#237;sticas de los receptores de somatostatina&#44; c&#243;mo debe realizarse la selecci&#243;n de pacientes candidatos a terapia con p&#233;ptidos radiomarcados &#40;PRRT&#41;&#44; si el paciente cumple los criterios para beneficiarse del tratamiento&#44; con los m&#237;nimos efectos adversos posibles&#44; el protocolo de administraci&#243;n&#44; seguimiento y evaluaci&#243;n de respuesta&#46; Tambi&#233;n se desarrollan los estudios de imagen funcional necesarios para explorar la biolog&#237;a del tumor e individualizar el tratamiento&#44; que constituyen la piedra angular para el desarrollo de la teragnosis&#46;</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Se est&#225;n desarrollando ensayos cl&#237;nicos para definir mejor la posici&#243;n de PRRT dentro del amplio panorama terap&#233;utico&#44; y entre las perspectivas de futuro hay varias l&#237;neas de investigaci&#243;n para mejorar la tasa de respuesta objetiva y la supervivencia con PRRT&#44; centradas en el desarrollo de nuevos agonistas y antagonistas del receptor de somatostatina&#44; nuevos radion&#250;clidos y terapias combinadas radiosensibilizantes&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">En conclusi&#243;n la PRRT es un tratamiento bien tolerado&#44; seguro y con efectos secundarios agudos&#44; generalmente leves y autolimitados&#44; que constituye una gran herramienta terap&#233;utica que debe secuenciarse en el mejor momento de la evoluci&#243;n de la enfermedad de los pacientes con TNE&#46; Los pacientes candidatos a la PRRT deben ser valorados siempre por un comit&#233; cl&#237;nico multidisciplinar&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Prado-Wohlwend S&#44; Bernal-Vergara JC&#44; Utrera-Costero A&#44; Ca&#241;&#243;n-S&#225;nchez JR&#44; Agudelo-Cifuentes M&#44; Bello-Arques P&#46; Terapia con p&#233;ptidos radiomarcados con &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE&#46; Rev Esp Med Nucl Imagen Mol&#46; 2022&#59;41&#58;54&#8211;64&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A&#46; Maximum intensity projection &#40;MIP&#41; of a &#91;<span class="elsevierStyleSup">68</span>Ga&#93;Ga-DOTA-TOC PET&#47;CT study in a patient with pancreatic NET with Ki-67 of 20&#37;&#46; Multiple and intense uptakes are observed in the pancreas&#44; liver&#44; supradiaphragmatic lymph nodes&#44; abdominal implants&#44; and bone lesions in relation to the overexpression of somatostatin receptors&#46; B and C&#46; Scan of distribution in anterior and posterior projection at 24&#8239;h after the administration of 7&#46;4&#8239;GBq of &#91;<span class="elsevierStyleSup">177</span>Lu&#93;Lu-DOTA-TATE&#46; The uptake is concordant with all the lesions visualized in the &#91;<span class="elsevierStyleSup">68</span>Ga&#93;Ga-DOTA-TOC PET&#47;CT&#46;</p>"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">NET&#58; neuroendocrine tumors&#44; NEC&#58; neuroendocrine carcinomas&#44; MiNEN&#58; mixed non-neuroendocrine - neuroendocrine neoplasias&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Classification of gastroenteropancreatic NET&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mitotic rate &#40;mitosis&#47;2 mm<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">G1 NET&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Well differentiated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G2 NET&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Well differentiated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intermediate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#8722;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#37;&#8722;20&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G3 NET&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Well differentiated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;20&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Small-cell NEC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Poorly differentiated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;20&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Large cell NEC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Poorly differentiated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;20&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MiNEN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Well or poorly differentiated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2794679.png"
              ]
            ]
            1 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Classification pulmonary NET&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Morphology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cytology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mitosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Typical carcinoid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carcinoid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Atypical carcinoid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carcinoid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#8722;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Large cell NEC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neuroendocrine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Large cell &#40;&#62;20&#8239;&#956;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;10 &#40;&#177;70&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Microcytic carcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neuroendocrine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Small cell &#40;&#60;20&#8239;&#956;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;10 &#40;&#177;80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2794682.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">2019 classification of the World Health Organization of gastroenteropancreatic neuroendocrine tumors and the 2015 classification of pulmonary neuroendocrine tumors&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0030"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Krenning score&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Uptake&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SSTR-RADS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Findings&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Absence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benign lesion by biopsy or imaging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Very low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Soft tissue or atypical bone lesion of metastatic NET&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Slightly less than or equal to hepatic uptake&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doubtful lesion of malignancy in soft tissue or bone &#40;due to doubtful uptake&#44; intense uptake in atypical localization or lesions suggestive of malignancy but without uptake&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Greater than hepatic uptake&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intense uptake in typical NET localization without findings in conventional imaging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Greater than splenic uptake&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intense uptake in typical NET localization with findings in conventional imaging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2794680.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Krenning scale of intensity and uptake and integrated SSTR-RADS evaluation&#46; Those localized in the shaded region are candidates to PRRT for SSTR expression&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0035"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Presentation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Adverse event&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Follow-up and&#47;or treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="17" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Acute</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nausea&#44; headache&#44; abdominal disturbances&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Use low osmolarity solution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Consider antiemetic before and&#47;or during infusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Congestive heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Slow infusion of amino acids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Electrolyte imbalance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- Use low osmolarity solution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Catecholaminergic crisis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Premedication&#58; -Avoid corticosteroids -Ondansetron 4&#8239;mg&#8239;orally -Consider adrenergic &#945; and &#946; blockade if high risk&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Catecholaminergic crisis&#58; -Stop infusion of the radiopharmaceutical -Maintain volume with saline solution 0&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-If hypertension&#58; captopril 50&#8239;mg&#8239;orally&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Severe hypertension&#58; nitroprusiate 0&#46;5&#8211;3 mcg&#47;kg&#47;min&#59; phentolamine 1&#8239;mg &#40;if necessary&#44; repeat bolus of 5&#8239;mg&#41;&#59; Nicardipine 5&#8239;mg&#47;h in continuous perfusion until control of blood pressure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Hypertension &#43; tachycardia&#58; Labetalol&#58; infusion 20&#8239;mg&#47;IV in slow bolus &#40;maximum 300&#8239;mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-If cardiac arrhythmia&#58; lidocaine 50&#8722;100 IV&#59; Esmolol 50&#8722;200 mcg&#47;kg&#47;min IV&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Consider intensive care unit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carcinoid crisis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Premedication &#40;if high risk&#41;&#58; -Dexamethasone 4&#8722;8&#8239;mg -Ondansetron 4&#8239;mg&#8239;orally -Octreotide 100 mcg SC &#243; 50 mcg IV -AntiH1 &#40;dexchlorpheniramine 5&#8239;mg IV in slow infusion&#41; -AntiH2 &#40;ranitidine 50&#8239;mg IV in slow infusion&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carcinoid crisis&#58; -Stop infusion of the radiopharmaceutical -Octreotide 100&#8722;500 mcg SC or IV&#44; maintain 50&#8722;100 mcg&#47;h -Hydrocortisone or methylprednisolone 1&#8722;2&#8239;mg&#47;kg&#47;IV in slow infusion -If hypotension&#58; phenylephrine or vasopressin -if hypertension&#58; adrenergic &#945; and &#946; blockade -Maintain volume&#58; Infusion of saline solution 0&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Flushing&#44; pruritus&#44; facial or uvula edema&#58; -Dexchlorpheniramine 5&#8722;10&#8239;mg IV slow infusion&#44; maintain 5&#8239;mg&#47;6&#8239;h -Ranitidine 50&#8239;mg IV slow infusion&#44; maintain 50&#8239;mg&#47;6&#8722;8&#8239;h&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diarrhea -Monitor electrolytes&#44; renal function&#44; hemostasis&#44; and transaminases - Hydro-electrolytic correction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bronchospasm -Avoid adrenergic &#946; stimulus -Corticosteroids&#58; Hydrocortisone&#44; methylprednisolone&#44; beclomethasone&#44; or fluticasone&#46; -Ipratropium bromide 50&#8722;60 mcg inhalation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tumoral lysis syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Specific treatment&#46; Consider intensive care unit&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subacute&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hematologic toxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Periodic control with hemogram&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="7" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Delayed</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nephrotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Periodic control of renal function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatic toxicity&#44; ascites&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Diet low in salt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Treatment with diuretics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Paracentesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Peritoneal-venous shunt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Loss of hair&#44; asthenia&#44; reduction of appetite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Transitory alteration of fertility&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Based on the patient&#44; consider sperm banks prior to therapy&nbsp;\t\t\t\t\t\t\n
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