¿Constituirán en el futuro los radioligandos de 68Ga-PSMA la única elección de la Medicina Nuclear para el cáncer de próstata? Actualización clínica / Will 68Ga PSMA-radioligands be the only choice for nuclear medicine in prostate cancer in the near future? A clinical update

El cáncer de próstata (CaP) representa el tumor maligno más frecuente en los varones, pero según las directrices de la European Association of Urology (EAU) no deben realizarse cribados masivos para el diagnóstico de CaP debido a problemas relacionados con el sobrediagnóstico y sobretratamiento. El diagnóstico clínico precoz es posible, principalmente basado en el tacto rectal y la determinación del antígeno prostático específico (PSA). Sin embargo, el único test que puede determinar la presencia de un CaP es la biopsia guiada por ecografía, obteniendo múltiples muestras, la cual tiene un elevado valor pronóstico. En este contexto, la imagen diagnóstica juega un importante papel tal como lo confirmó la EAU, que en una actualización de 2016 de su guía clínica sobre CaP estableció la importancia de la tomografía por emisión de positrones (PET) con 11C- o 18F-colina combinada con la tomografía computarizada (TC) para individualizar la recidiva local, la afectación de ganglios linfáticos y la diseminación metastásica en todos los estadios. En consecuencia, en 2017, la European Association of Nuclear Medicine (EANM) junto con la Society of Nuclear Medicine and Molecular Imaging (SNMMI) compartieron nuevas directrices para la PET/TC con 68Ga-antígeno de membrana prostático específico (PSMA) para ayudar a los médicos en la recomendación, realización e interpretación de los estudios PET/TC en pacientes con CaP. De esta manera, el objetivo de este «artículo de evidencia» es definir el algoritmo diagnóstico actual en el CaP para incrementar el nivel de confianza global en el enfoque de un tema tan crucial (AU)

Prostate Cancer (PCa) represents the most common malignant tumor in men but according to the European Association of Urology (EAU) guidelines, a mass screening for PCa diagnosis should not be performed due to over-diagnosis and over-treatment related problems. An early clinical diagnosis is possible, mainly based on digital rectal examination and Prostatic Specific Agent (PSA) testing. However, the only mandatory test to define the presence of PCa is ultrasound guided-biopsy, obtained on multiple samples, which has also a high prognostic value. In this context, diagnostic imaging plays an important role as confirmed by EAU that in a 2016 update of their guidelines on PCa stated the importance of Positron Emission Tomography (PET) with 11C- or 18F-choline combined with computed tomography (CT) to identify local relapse, lymph node involvement and metastatic spread at all stages. Consequently, in 2017, the European Association of Nuclear Medicine (EANM) together with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) published new guidelines for 68Ga-Prostate Specific Membrane Antigen (PSMA) PET/CT to help physicians in the recommendation, execution and interpretation of PET/CT scans in patients with PCa. Thus, the aim of this ‘evidence paper’ is to define the current diagnostic algorithm in PCa in order to increase the general level of confidence in approaching such a crucial topic (AU)

Will 68Ga PSMA-radioligands be the only choice for nuclear medicine in prostate cancer in the near future? A clinical update. / ¿Constituirán en el futuro los radioligandos de 68Ga-PSMA la única elección de la Medicina Nuclear para el cáncer de próstata? Actualización clínica.

Prostate Cancer (PCa) represents the most common malignant tumor in men but according to the European Association of Urology (EAU) guidelines, a mass screening for PCa diagnosis should not be performed due to over-diagnosis and over-treatment related problems. An early clinical diagnosis is possible, mainly based on digital rectal examination and Prostatic Specific Agent (PSA) testing. However, the only mandatory test to define the presence of PCa is ultrasound guided-biopsy, obtained on multiple samples, which has also a high prognostic value. In this context, diagnostic imaging plays an important role as confirmed by EAU that in a 2016 update of their guidelines on PCa stated the importance of Positron Emission Tomography (PET) with 11C- or 18F-choline combined with computed tomography (CT) to identify local relapse, lymph node involvement and metastatic spread at all stages. Consequently, in 2017, the European Association of Nuclear Medicine (EANM) together with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) published new guidelines for 68Ga-Prostate Specific Membrane Antigen (PSMA) PET/CT to help physicians in the recommendation, execution and interpretation of PET/CT scans in patients with PCa. Thus, the aim of this 'evidence paper' is to define the current diagnostic algorithm in PCa in order to increase the general level of confidence in approaching such a crucial topic.

Radioguided thyroidectomy for follicular tumors: Multicentric experience.

BACKGROUND: The diagnosis of thyroid nodular diseases requires an integrated approach that has been widely established over the past years. This strategy includes: ultrasonography (US) with; implemented Color-Power-Doppler, conventional scintigraphy also with positive indicators, specific pathological studies targeted by immunohistochemically-assays, and the fine needle; aspiration biopsy (FNAB), which, usually, in case of "Follicular Lesions" (10-20%) findings is; unable to distinguish carcinoma from follicular adenoma, then indicating the necessity of surgery to; obtain a correct diagnosis. The aim of this study was to evaluate the role of the scintigraphy with; positive indicators, both preoperatively in diagnostic approach of the thyroid nodules and; intraoperatively as a guide to the extension of the surgical excision. METHODS: On 4482 Thyroidectomy performed, we selected 360 cases of follicular neoplasms (192; females and 168 males). In the preoperative phase, these patients underwent 99 m Tc-sestaMIBI; scintigraphy with both early (10 min) and late (2 h) image acquisition, which were later; compared to the ones obtained by image subtraction of means 99 m Tc-pertechnetate. Following the; sestamibi administration before intervention, we selected the most up-taking nodularity with the; assistance of a specific surgical probe (Neoprobe), quantifying uptake with relation to the surgical pathology, for an amount of 324 total thyroidectomies and 36 hemi thyroidectomies. RESULTS: In all cases of multinodular goiter the benign nodules showed an intraoperative low sestamibi uptake whereas follicular carcinomas showed both a high preoperative uptake and, as a; percentage, the highest values of intraoperative uptake; on the other hand, follicular adenomas had; both pre-and intraoperative mean values of uptake. On the contrary, papillary carcinomas only; showed a mild uptake. CONCLUSIONS: Preoperative sestamibi scintigraphy confirmed its importance in improving the information obtained through different diagnostic investigations. Also intraoperatively, it pointed; out high-risk nodules more accurately. Therefore, radio (Sestamibi) guided surgery could have an; interesting rule in the thyroid follicular lesion treatment.

18FNa-fluoride has a higher extraction with respect to 99mTc-methylene diphosphonate: mismatch in a case of meningioma / El 18F-fluoruro sódico (18FNa) muestra una mayor extracción que el 99mTc-metilen-difosfonato: discordancia en un meningioma

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Structural, pathophysiological and clinical aspects of diagnostic imaging in breast recurrence: the breast after treatment.

In the last decades the outcome of women with breast cancer has been significantly modified partially as a result of screening which has facilitated earlier diagnosis and consequently allowed a conservative surgical approach. Today diagnostic imaging is generally based on Mammography (Mx), with a minor role for ultrasounds and Magnetic Resonance (MR). In this scenario, dominated by morphostructural techniques, there is a secondary role for radionuclide procedures both using gamma emitters or Positron Emission Tomography (PET) with F-18 Fluorodeoxyglucose (FDG) or other radiotracers beyond FDG. After surgery and allied treatments, including radiotherapy, the diagnosis of breast recurrence has become a difficult challenge, because of the several factors simultaneously and/or sequentially involved. In the diagnosis of local recurrence, Mx remains the first diagnostic step together with a clinical visit, as alternative approaches yield more unsatisfactory results. Nevertheless as Mx is affected by a low sensitivity, it is important to better evaluate the capabilities of functional imaging utilizing MR and Nuclear Medicine, to allow an earlier and more accurate detection. In this paper we analyze structural, pathophysiological and the clinical background to diagnostic imaging in local breast recurrence to better understand basic problems, to facilitate more effective utilization of diagnostic tools.

Questions and answers: what can be said by diagnostic imaging in neuroendocrine tumors?

The neuroendocrine tumors (NET) of the gastro-entero-pancreatic area (GEP) represent a heterogeneous group of malignancies from the histologic, clinico-laboratoristic (functioning and non-functioning variants), and therapeutic point of view. It is an issue becoming more frequent for the diagnostic imager, being radiologist as well as nuclear physician. Imaging (together with biopsy) plays a key role in the diagnostic assessment and staging (including grading and prognostic definition), in evaluating response to treatment, and in follow-up of GEP-NET. Multislice computed tomography (MSCT), octreoscan and PET-CT are the most widely diffuse and accurate imaging modalities employed in this setting. Other methods, such as Magnetic Resonance and Endoscopic Ultrasound, may also play a significant role.

Pathophysiological premises to radiotracers for bone metastases.

Aim of our paper is to review the most important radio-compounds that can be successfully used to detect and/or characterize bone metastases. From a didactic point of view, we made a distinction between two main categories , the first allowing to individuate bone's reaction (osteotropic agents), the second trying to detect metastatic tumor cells (oncotropic agents). A wide description of the most diffuse Tc-99m diphosphonates , including analysis of uptake mechanisms and pharmacokinetics, is followed by a brief report on pathophysiological premises to the clinical use of F-18 fluoride and of specific (radioiodine, radiolabeled somatostatin or cathecolamine analogues) or non specific, as Tc-99m sestamibi, F-18 fluorodeoxhyglucose, F-18 choline, F-18 thymidine) oncotropic agents. At the end, the possibility to use diagnostic radiotracers to act both in recruiting patients with bone metastases undergoing radionuclide therapy and for their dosimetric evaluation is also discussed.

Less frequent requests for In-111 pentreotide and its brothers of endocrinological interest.

The somatostatin receptor scintigraphy (SRS), using octreotide radiolabelled with 111In (octreoscan, OCTs), is a consolidated diagnostic procedure in patients with neuroendocrine tumors. A higher accuracy has been demonstrated with single photon emission computed tomography-CT, while a further improvement has been obtained with positron emission tomography (PET)-CT, using somatostatin analogues radiolabeled with 68Ga, significantly increasing the number of detected lesions. Although the well-known presence of an OCTs uptake in many benign diseases, when in an active phase, the application of SRS in these patients did not find any clinical relevance yet. In this paper we discuss two fields of endocrinological interest where SRS could play a clinical role. In patients with Graves exophtalmos, the capability to differentiate between active and non-active disease can be helpful in define prognosis and therapeutic strategies. In patients with endocrine paraneoplastic syndromes (PNS), SRS can help in finding the underlying neoplasm, contributing to its characterization as premise to a therapeutic choice. The possible role of a surgery guided by OCTs is also explained and suggested. The incremental value of PET-CT with Ga-68 peptides is hypothesized to reduce the number of unknown neoplastic lesions frequently present in patients with PNS.

The non tumour uptake of (111)In-octreotide creates new clinical indications in benign diseases, but also in oncology.

The use of somatostatin (SS) analogues in humans takes advantage by the availability of many related chemical forms that can be used for receptor therapy and, after radiolabelling, for diagnostic imaging and radionuclide therapy. The first proposed radiocompound, yet clinically widely diffuse, has been (111)In-octreotide (OCT), followed by positron emission tomography (PET) and beta emitter tracers. The main field of clinical applications is in neuroendocrine tumours (NET), starting by the demonstration of SS receptors (SSR) on the majority of NET, particularly on gastroenteropancreatic (GEP) tumours. Uptake of SS analogues can also be due to a SSR expression on non malignant cells when activated, as lymphocytes, macrophages, fibroblasts , vascular cells. Because of this uptake clinical indications can be found also in active benign diseases, as Grave's ophthalmopathy, rheumatoid arthritis, histiocitosis, sarcoidosis, idiopatic pulmonary fibrosis. Moreover, these cells can also determine the OCT in vivo uptake in tumours non expressing in vitro SSR, as non-snall cell lung cancer (NSCLC). Because of a different kinetic respect to SCLC a differential histotype diagnosis could be obtained. Starting from this premise OCT can also allows radioguided surgery in tumours non expressing SSR. Finally a relevant clinical role can be defined in the a priori recruitment and as marker of therapeutic efficacy in all the therapeutic strategies utilizing SSR, both in malignant and benign diseases.

Plurifocal breast cancer and double lymphatic spread.

BACKGROUND: Sentinel node (SN) has been proved to be a reliable technique in predicting the lymph nodes state of the axilla in breast cancer. For the majority of the authors the intradermal and peritumoral injection is the best way. PATIENTS AND METHODS: Our experience, from 1997, includes 587 cases of SN in women with resectable breast cancer less than 3 cm of diameter. We performed the lymphoscintigraphy after a peritumoral injection of radioactive tracer and, if the lesion was superficial, we associated an intradermal injection on the skin above the lesion itself. Two patients had multifocal right breast cancer. We did two separate injections around each tumor. RESULTS: The radioactive tracer spread towards the internal mammary chain and homolateral axillary nodes. CONCLUSIONS: We consider the peritumoral injection as essential in tumors located deeply in the breast (under ultrasound guide if not palpable) together with intradermal injection in superficial ones. Using this technique the possibility of a mis-identification of the SN is reduced.

The present and future role of (111)In pentetreotide in the PET era.

Today, positron emission tomography (PET) using F-18 Fluoro-deoxyglucose (FDG) is, when available, the most important nuclear medicine procedure applied to oncology. Nevertheless, 2 main reasons for the clinical use of somatostatin analogues labeled with single photon emitting radionuclides are: a) the low accuracy of PET-FDG in neuroendocrine tumors (NET); b) the expression of somatostatin receptors (sstr) in most cells deriving from so-called neuroendocrine dispersed cells. The latter forms the premise for the use of radiolabeled somatostatin analogues, and (111)In pentetreotide (Octreo-scan) in particular, in the diagnosis of NET and other pathological conditions, including some benign diseases. Alongside diagnosis, staging and follow-up of NET, somatostatin analogues, whether radiolabeled or not, can have a role in evaluating prognosis and predicting therapeutic efficacy in cancer patients. Interesting indications have emerged with radioguided surgery and in diagnosing the activity of disease in patients with Graves' disease (exophthalmos), sarcoidosis, and rheumatoid arthritis. The pathophysiological premises to imaging, starting from an analysis of cells expressing sstr, binding affinity of octreotide for sstr, in vivo uptake of Octreoscan in lesions expressing or not sstr are discussed, as is the possible role of quantitative receptor scintigraphy in improving diagnostic accuracy based on tumor expression of sstr.

Nuclear medicine in emergency.

The role of a procedure depends not only on its own capabilities but also on a cost/effective comparison with alternative techniques giving similar information. Starting from the definition of emergency as a sudden unexpected occurrence demanding immediate action, the role of nuclear medicine (NM) is difficult to identify if it is not possible to respond 24 h a day, 365 days a year, to clinical demands. To justify a 24 h NM service it is necessary to reaffirm the role in diagnosis of pulmonary embolism in the spiral CT era, to spread knowledge of the capabilities of nuclear cardiology in reliably diagnosing myocardial infarction (better defining admission and discharge to/from the emergency department), to increase the number of indications. Radionuclide techniques could be used as first line, alternative, complementary procedures in a diagnostic tree taking into account not only the diagnosis but also the connections with prognosis and therapy in evaluating cerebral pathologies, acute inflammation/infection, transplants, bleeding, trauma, skeletal, hepatobiliary, renal and endocrine emergencies, acute scrotal pain.

Nuclear medicine in diagnosis, staging and follow-up of thyroid cancer.

Diagnostic strategy in thyroid cancer is conditioned by epidemiological, pathophysiological, cost-effective issues changing with age and countries. Nuclear medicine has a role mainly in differentiated carcinomas, i.e. in the large majority of thyroid cancers. In diagnosis of thyroid nodule (99m)Tc-perthecnetate is indicated in patients with low TSH levels, multinodular goiter, solid nodules at US negative at FNA. Radiolabeled somatostatin analogs or Metaiodobenzylguanidine (MIBG) can be used in suspicion of medullary carcinoma. There is no role in staging. WBS with 131I has a role after surgical resection of the thyroid gland and it is no more suggested before ablative therapy, because of the possible stunning effect. In the follow-up thyroglobulin (Tg) test is mandatory both after therapy withdrawal or after rhTSH administration. Some authors already suggest to use this test alone, as 1st step, in patients with differentiated carcinoma at low risk of recurrence, but this approach is not yet generally accepted and it has not yet been validated in tumors at intermediate/high risk. WBS with 131I is ever indicated when autoantibodies can affect reliability of Tg values and in presence of high Tg levels to better define a radiometabolic therapy. In case of negative WBS, PET-FDG can be proposed. In WBS, 123I can be an alternative to 131I, but it is not yet generally accepted mainly because of its higher costs. The clinical use of rhTSH to increase accuracy both of Tg and WBS can be already accepted in patients at high risk following hypothyroidism, with a worst prognosis or a low pituitary response.

The development of diving bradycardia in bottlenose dolphins (Tursiops truncatus).

Bradycardia is an important component of the dive response, yet little is known about this response in immature marine mammals. To determine if diving bradycardia improves with age, cardiac patterns from trained immature and mature bottlenose dolphins ( Tursiops truncatus) were recorded during three conditions (stationary respiration, voluntary breath-hold, and shallow diving). Maximum (mean: 117+/-1 beats.min(-1)) and resting (mean: 101+/-5 beats.min(-1)) heart rate (HR) at the water surface were similar regardless of age. All dolphins lowered HR in response to apnea; mean steady state breath-hold HR was not correlated with age. However, the ability to reduce HR while diving improved with age. Minimum and mean steady state HR during diving were highest for calves. For example, 1.5-3.5-year-old calves had significantly higher mean steady state diving HR (51+/-1 beats.min(-1)) than 3.5-5.5-year-old juveniles (44+/-1 beats.min(-1)). As a result, older dolphins demonstrated greater overall reductions in HR during diving. Longitudinal studies concur; the ability to reduce HR improved as individual calves matured. Thus, although newly weaned calves as young as 1.7 years exhibit elements of cardiac control, the capacity to reduce HR while diving improves with maturation up to 3.5 years postpartum. Limited ability for bradycardia may partially explain the short dive durations observed for immature marine mammals.

[Modulation of the axillary lymph node dissection in breast cancer]. / La modulazione della dissezione linfonodale dell'ascella nel carcinoma mammario. Nostra esperienza.

UNLABELLED: Several studies showed the reliability of the sentinel lymph node (SN) technique in the evaluation of the N parameter in breast cancer so much to induce surgeons to limit the axillary dissection to the biopsy of the SN alone (SNB) in case this is negative to the extemporaneous examination. After a period of focusing on the identification technique, biopsy and histological examination of the SN (October 97-January 98) always followed by a complete dissection of the three axillary node levels (ALND), we started a study to evaluate the reliability of a limited dissection of the 1st level of the axilla (FLND) in women with T < 3 cm, N0-1a, M0, that did not undergo any neoadjuvant treatment and in which the SN resulted free from metastases. We started this phase of the study in February 1998 till May 2001. In the present paper we show the results related to this period. MATERIALS AND METHODS: We enrolled 256 women with T < 3 cm, N0-1a, M0. In 49 cases we used vital dye, in 23 dye + radioguided surgery (RGS) and in 184 RGS only. The extemporaneous histological examination of the SN has been performed with thin sections, dyed with EE. When SN was negative to the intraoperative examination, we limited the dissection to the 1st level of the axilla, except that in 3 patients, with SN located to the 2nd level, in which we did an ALND. The FLND has been performed in 17 cases with a minimally invasive technique. The definitive histological examination of the SN always included the immunohistochemistry. If the SN was positive, usually underestimated to the intraoperative examination, the patients had an adjuvant chemotherapy. RESULTS: In 203/207 patients (98.1%) SN was found to the pre-operative lymphoscintigraphy. During surgery the SN was identified in 46/49 (94%) using the vital dye, in 22/23 (96%) using the vital dye + RGS and in 176/179 (98.3%) using RGS. To the extemporaneous histological examination SN was negative in 140, metastatic in 101; to the histological definitive results of the SN we noticed 6 false negative, since others lymph nodes than SN were positive (4 cases) or for evidence of micrometastases at the immunohistochemistry which were not detected at the extemporaneous examination (2 cases). On 107 cases of N+ the SN was the only metastatic lymph node in 42 (39.3%). The false negative percentage was 5.6% and the diagnostic accuracy of the SNB was 97.5%. In the group treated with FLND we only noticed two cases of light lymphedema (1.4%). CONCLUSIONS: Our results are in concordance with the international literature and they induced us, from June 2001, to begin a new phase of the study in which we limit the dissection of the axilla to the SN only, if not metastatic, in women with T1 breast carcinoma.

[Immunological imaging using tagged octreotide]. / Imaging immunologico con octreotide marcato.

The diagnostic use of radiolabeled octreotide has shown that somatostatin receptor scintigraphy can be successfully used in various neoplasms with a strictly neuroendocrine derivation, because of a good correlation between in vitro receptor expression and in vivo uptake. Moreover, 111In-Octreotide uptake has been demonstrated in various pathologies owing to the receptorial expression on cell elements such as lymphocytes, fibroblasts and endothelium. Although main diagnostic role is in neuroendocrine tumours, octreotide can be also used to obtain an immunological imaging in other fields. The presence of type 2 receptors on activated lymphocytes has stimulated the use of somatostatin in both the treatment and diagnosis of disease activity in patients with Graves' ophthalmopathy. Somatostatin analogs have been successfully used for the treatment and imaging of various tumours of thymic origin. Our research group has evaluated the possible clinical role of octreotide scintigraphy in paediatric patients with thymic hyperplasia after chemotherapy for lymphoma. Even if not routinely applicable, these approaches offer interesting diagnostic, prognostic and therapeutic prospects.

[Role of somatostatin analogs in the treatment of neuroendocrine tumours]. / Ruolo degli analoghi della somatostatina nella teapia dei tumori neuroendocrini.

Current therapeutic approaches in neuroendocrine tumours include surgery, radiotherapy and polychemotherapy. Different metabolic patterns of neuroendocrine tumours allow the use of a wide range of diagnostic options in nuclear medicine, due to the presence of a wide spectrum of radiotracers electively concentrating in these neoplasms. Nuclear medicine, and in particular 111In Octreotide (OCT) scintigraphy, 123I Methaiodobenzylguanidine (MIBG) and pentavalent 99mTc-DMSA (V-DMSA), together with biohumoral markers, are currently able to locate tumours also not detectable using traditional diagnostic techniques. Somatostatin analogs, such as octreotide have become increasingly important over the years in the treatment of patients with neuroendocrine tumours. At present the therapeutic use of somatostatin analogs can be schematised as 1) pharmacological treatment (with cold octreotide); 2) surgical treatment (radioguided surgery); 3) radiometabolic treatment (with marked octreotide). The development of new synthetic molecules and new radiocompounds will probably open up interesting scenarios in the near future.

[Role of radio-guided surgery with 111In-octreotide in the treatment of thoracic neoplasms]. / Ruolo della chirurgia radio-guidata con in-octreotide nel trattamento delle neoplasie toraciche.

The study evaluates the role of radio-guided surgery (RGS) with 111In-octreotide in the treatment of lung neoplasms. RGS with octreotide appears to be useful in surgery, above all during the intraoperative staging of the tumour; it can define with greater precision the extent of the resections extended towards the lung wall and ensure a radical approach in minimal lung resections.