Head-to-Head Comparison of 68Ga-PSMA-11 and 131I in the Follow-Up of Well-Differentiated Metastatic Thyroid Cancer: A New Potential Theragnostic Agent.

Introduction: Thyroid cancer is the main endocrine neoplasia worldwide, for which 131I therapy is the cornerstone treatment. One of the main problems of follow up in patients with this type of cancer, is the need for thyroglobulin stimulation, not to mention the poor availability of 123I or 124I, to perform studies with a higher degree of sensitivity. Prostatic Specific Membrane Antigen (PSMA) PET/CT has demonstrated to be quite useful in a diversified number of neoplasms, on behalf of its capacity of evaluating the extent of type II carboxypeptidase expression in vascular endothelium. The end point of this article is to assess whether this novel image method possesses applicability in thyroid neoplasms follow up, for diagnostic and potentially therapeutic purposes. Methods: We retrospectively evaluated well differentiated metastatic thyroid cancer patients, who underwent a post therapeutic 131I dose whole body scan (WBS) and complementary SPECT/CT, as well as 68Ga-PSMA-11 PET/CT. Results: Ten patients with differentiated thyroid cancer were included, of whom 80% were women and 20% men, mean age was 58 years old (± 11.6). Sixty-four metastatic lesions were analyzed, 67.19% had papillary histology and 32.81% were follicular type, the most affected site of metastases was bone in 57.81%, followed by lung 17.19%, lymph nodes 7.81%, postoperative thyroid bed 4.69%, brain 4.69% and others 7.81%. 68Ga PSMA-11 PET/CT detected 64/64 lesions, all of them also identified by computed tomography (CT), whereas 131I SPECT/CT detected 55/64 lesions. Discrepant lesions were localized in lung 44.4%, brain 22.2%, postoperative thyroid bed 11.1%, lymph nodes 11.1% and bone 11.1%. The degree of correspondence among observers was outstanding for both radiotracers, but close upon perfect for PSMA-11 (κ = 0.98; 95% CI, 0.80 - 0.91), as opposed to 131 I (κ = 0.86; 95% CI, 0.71 - 0.76). Conclusions: 68Ga-PSMA PET/CT showed an utterly superior capability for metastatic lesion detection when compared to 131I SPECT/CT. These findings suggest that PSMA PET/CT could possibly and precociously identify radioiodine refractoriness. PSMA uptake values not only expedite diagnosis, but also award it the ability to be used for therapeutic intents.

Hybrid (2D/3D) Dosimetry of Radiolabeled Gold Nanoparticles for Sentinel Lymph Node Detection in Patients with Breast Cancer.

Previously, we reported the preparation and preclinical studies of 99mTc-labeled gold nanoparticles-mannose (99mTc-AuNP-mannose) with potential for sentinel lymph node (SLN) detection by using nuclear medicine procedures. This study aimed to evaluate the biokinetics and hybrid (2D/3D) dosimetry of 99mTc-AuNP-mannose in five patients with breast cancer under a sentinel lymph node detection protocol. Anterior and posterior whole-body planar images (2D, at 0.5, 2, 6, and 24 h) and single-photon emission computed tomography (3D at 6.5 h)/computed tomography (SPECT/CT) images were acquired after 99mTc-AuNP-mannose administration (37 MBq). Through a hybrid quantification method, activity in tissues of interest at the different acquisition times was determined and integrated over time to obtain the total nuclear transformations (N), as well as the mean residence time, in each tissue. N values and the OLINDA code were used for estimating the internal radiation absorbed doses. Results demonstrated that 99mTc-AuNP-mannose successfully accumulates and remains up to 24 h in the sentinel lymph node without detectable migration to other lymph nodes and no side effects on patients. Negligible absorption of the radiolabeled nanoparticles into the circulatory system was observed, from which the radio-nanosystem is rapidly eliminated by kidneys. Hybrid (2D/3D) dosimetry evaluations showed equivalent doses to SLN, breast, and kidneys of 172.34, 5.32, and 0.08 mSv/37 MBq, respectively, with an effective dose of 2.05E - 03 mSv/MBq. The mean effective residence time in SLN was 0.92 h. This preliminary study indicates that the use of 99mTc-AuNP-mannose for successful SLN detection in patients is safe, producing an effective dose at the level recommended for diagnostic studies (<10 mSv).

Prognostic Impact of Direct 131I Therapy After Detection of Biochemical Recurrence in Intermediate or High-Risk Differentiated Thyroid Cancer: A Retrospective Cohort Study.

Background: Patients treated for intermediate- or high-risk differentiated thyroid carcinoma (DTC) and Thyroglobulin (TG) elevation during follow-up, require a diagnostic whole-body scan (DWBS) and if positive, 131I treatment. This approach can lead to a delay in treatment and increased costs. The purpose of this study is to compare the oncologic outcomes associated to administration of direct therapy with 131I at first biochemical recurrence. Methods: Retrospective cohort study of patients with intermediate- or high-risk DTC treated with total thyroidectomy, 131I ablation and who developed TG elevation during follow-up, between January 2007 and December 2015. Cohort A included patients who underwent a DWBS with 5 mCi of 131I, and if negative an MRI and/or 18FDG PET-CT prior to the therapeutic dosage, and cohort B included those who only received a therapeutic dosage of 131I, without a DWBS or extensive image studies. Main outcomes were second recurrence (SR) and disease-free survival (DFS). The diagnostic accuracy of DWBS was analyzed. Results: Cohorts A and B had 74 and 41 patients, each. By multivariate analysis, age, differentiation grade, TN classification, ablation dose, and performed DWBS (odds ratio 55.1; 95% CI 11.3-269) were associated with SR (p < 0.0001); age, male gender, ablation dose and performed DWBS (hazard ratio 7.79; 95% CI 3.67-16.5) were independent factors associated with DFS (p < 0.0001). DWBS diagnostic accuracy was 36.48%. Conclusion: 131I treatment in patients with DTC biochemical recurrence and no DWBS or extensive image studies is associated with a significantly lower frequency of SR and an increased DFS. The diagnostic accuracy of DWBS is low, and its clinical efficiency should be defined in prospective phase III studies.

99mTc-labeled PSMA inhibitor: Biokinetics and radiation dosimetry in healthy subjects and imaging of prostate cancer tumors in patients.

The prostate-specific membrane antigen (PSMA) is expressed in epithelial cells of the prostate and highly overexpressed in 95% of advanced prostate cancers. The aims of this study was to estimate the biokinetics and dosimetry of 99mTc-EDDA/HYNIC-iPSMA (99mTc-labeled PSMA inhibitor) in eight healthy subjects and evaluate its usefulness as a tumor-imaging agent in eight prostate cancer patients. METHODS: 99mTc-EDDA/HYNIC-iPSMA was obtained from a lyophilized formulation with radiochemical purities >98%, determined by reversed-phase HPLC and ITLC-SG analyses. Whole-body images from eight healthy subjects were acquired at 20min, and at 2, 6 and 24h after 99mTc-EDDA/HYNIC-iPSMA administration. Regions of interest (ROIs) were drawn around the source organs on each time frame. Each ROI was corrected by background, attenuation, scattered radiation and physical decay. The image sequence was used to extrapolate the 99mTc-EDDA/HYNIC-iPSMA time-activity curves of each organ to adjust the biokinetic model and calculate the total number of disintegrations (N) that occurred in the source regions. N data were the input for the OLINDA/EXM code to calculate internal radiation doses. In eight prostate cancer patients with histologically confirmed cancer, whole-body SPECT/CT images were obtained at 3h. RESULTS: The blood activity showed a half-life value of 4.98min for the fast component (T1/2α=ln2/8.34), 2.49h for the first slow component (T1/2ß=ln2/0.278), and 9.24h for the second slow component (T1/2γ=ln2/0.076). Images from patients showed an average tumor/background ratio of 8.99±3.27 at 3h. The average equivalent doses calculated for a study using 740MBq were 3.80, 7.06, 9.69, 10.70, and 28.80mSv for the breast, spleen, salivary glands, liver, and kidneys respectively, with an effective dose of 3.42±0.78mSv. CONCLUSIONS: All the absorbed doses were comparable to those known for most of the 99mTc studies. 99mTc-EDDA/HYNIC-iPSMA obtained from kit formulations showed high tumor uptake in patients with malignant lesions, making it a promising imaging radiopharmaceutical to target site-specific prostate cancer.

Relación entre ganglio centinela positivo y el espesor de Breslow en pacientes con melanoma cutáneo primario / Relationship between positive sentinel lymph node and Breslow's depth in patients with primary cutaneous melanoma

Introducción: es sabido que el pronóstico del melanoma cutáneo depende, entre otros factores, de la existencia de diseminación linfática a ganglios. La biopsia del ganglio centinela busca identificar metástasis ganglionares subclínicas. Objetivo: el presente estudio tuvo por objetivo analizar la asociación entre la presencia de ganglio centinela positivo, identificado mediante rastreo con radioisótopo 99mTc-coloide de Renio, y el espesor de Breslow hallado en la lesión primaria a nivel cutáneo. Metodología: se analizaron 52 pacientes. Se realizó la búsqueda del ganglio centinela por el método de rastreo con radioisótopo 99mTc-coloide de Renio y posterior biopsia del mismo, en pacientes tratados en el Instituto Nacional de Cancerología de México, entre enero de 2015 a agosto de 2016, con diagnóstico de melanoma cutáneo y espesor de Breslow mayor o igual a 1mm o con menor a 1mm y otros criterios de riesgo como la ulceración. Aquellos con biopsia positiva fueron sometidos a linfadenectomía. Además, se recogieron las siguientes variables: sexo, edad, localización, tipo de melanoma, espesor de Breslow y ulceración. Resultados: la edad media de la muestra fue 57 ± 15 años. El 63,5% de los pacientes fue del sexo masculino. El tipo histológico más frecuente fue el melanoma de extensión superficial (69,2%). Se detectó positividad del ganglio centinela en 46,2% y 28,8% presentó Breslow >4,0 mm. Se encontró relación entre la presencia de ganglio centinela positivo y espesor de Breslow (p=0,007). Conclusiones: a medida que aumenta el espesor de Breslow, lo hace también el encuentro de metástasis en ganglio centinela. Se recomienda realizar estudios de casos y controles para evaluar el factor predictivo que puede llegar a tener el encontrar ganglio centinela positivo.

Introduction: It is known that the prognosis of cutaneous melanoma depends, among other factors, on the existence of lymphatic spread to lymph nodes. Sentinel node biopsy seeks to identify subclinical lymph node metastases. Objective: The present study aimed to analyze the association between the presence of positive sentinel lymph node, identified by Rhenium 99mTc-colloid radioisotope tracing, and the Breslow´s depth found in the primary lesion at the cutaneous level. Methodology: 52 patients were analyzed. The sentinel lymph node was searched by the rhenium 99mTc-colloid radioisotope and subsequent biopsy of it in patients treated at the Instituto Nacional de Cancerología of Mexico, between January 2015 and August 2016, with a diagnosis of cutaneous melanoma and Breslow's depth greater-than or equal to 1mm or less-than 1mm and other risk criteria such as ulceration. Those patients with positive biopsy underwent lymphadenectomy. In addition, the following variables were collected: sex, age, location of the lesion, type of melanoma, Breslow's depth, and ulceration. Results: Mean age of the sample was 57±15 years. 63.5% of the patients were male. The most frequent histological type was superficial spreading melanoma (69.2%). 46.2% had positive sentinel lymph node. 28.8% presented Breslow >4.0 mm. A relationship was found between the presence of positive sentinel lymph node and Breslow's depth (p=0.007). Conclusions: As Breslow's depths increases, so does the metastasis encounter in sentinel lymphs nodes. It is recommended to carry out case-control studies to evaluate the predictive factor that may result in finding a positive sentinel lymph node.

Kit preparation and biokinetics in women of 99mTc-EDDA/HYNIC-E-[c(RGDfK)]2 for breast cancer imaging.

BACKGROUND: In breast cancer, α(ν)ß(3) and/or α(ν)ß(5) integrins are overexpressed in both endothelial and tumour cells. Radiolabelled peptides based on the Arg-Gly-Asp (RGD) sequence are radiopharmaceuticals with high affinity and selectivity for these integrins. The RGD-dimer peptide (E-[c(RGDfK)]2) radiolabelled with (99m)Tc has been reported as a radiopharmaceutical with a 10-fold higher affinity for the α(ν)ß(3) integrin compared with the RGD-monomer. Ethylenediamine-N,N'-diacetic acid (EDDA) is a hydrophilic molecule that may favour renal excretion when used as coligand in the (99m)Tc labelling of hydrazinonicotinamide (HYNIC) peptides and can easily be formulated in a lyophilized kit. AIM: The aim of this study was to establish a biokinetic model for (99m)Tc-EDDA/HYNIC-E-[c(RGDfK)]2 prepared from lyophilized kits and evaluate its dosimetry as a tumour-imaging agent in seven healthy women and three breast cancer patients. MATERIALS AND METHODS: (99m)Tc labelling was performed by adding sodium pertechnetate solution and 0.2 mol/l phosphate buffer (pH 7.0) to a lyophilized formulation containing E-[c(RGDfK)]2, EDDA, tricine, mannitol and stannous chloride. The radiochemical purity was evaluated using reverse-phase high-performance liquid chromatography and instant thin-layer chromatography on silica gel analyses. Stability studies in human serum were carried out using size-exclusion high-performance liquid chromatography. In-vitro cell uptake was tested using breast cancer cells (MCF7, T47D and MDA-MB-231) with blocked and nonblocked receptors. Biodistribution and tumour uptake were determined in MCF7 tumour-bearing nude mice with blocked and nonblocked receptors, and images were obtained using a micro-SPECT/PET/CT. Whole-body images from seven healthy women were acquired at 0.5, 1, 3, 6 and 24 h after (99m)Tc-EDDA/HYNIC-E-[c(RGDfK)]2 administration with radiochemical purities greater than 94%. Regions of interest were drawn around the source organs at each time frame. Each region of interest was converted to activity using the conjugate view counting method. The image sequence was used to extrapolate the (99m)Tc-EDDA/HYNIC-E-[c(RGDfK)]2 time-activity curves of each organ to adjust the biokinetic model and calculate the total number of disintegrations (N) that occurred in the source regions. N data were the input for the OLINDA/EXM code to calculate internal radiation dose estimates. In three breast cancer patients with histologically confirmed cancer, static images were obtained at 1 h in the supine position with hands placed behind the head. RESULTS: (99m)Tc-EDDA/HYNIC-E-[c(RGDfK)]2 obtained from lyophilized kits demonstrated high stability in human serum and specific cell receptor binding. The biodistribution data from mice showed rapid blood clearance, with both renal and hepatobiliary excretion, and specific binding towards α(ν)ß(3) integrins in the MCF7 tumours. In women, the blood activity showed a half-life value of 1.60 min for the fast component (T1/2α = ln2/26.01) and half-life values of 1.0 h for the first slow component (T1/2ß = ln2/0.69) and 4.03 h for the second slow component (T1/2γ = ln2/0.16). Images from patients showed an average tumour/heart (blood) ratio of 3.61 ± 0.62 at 1 h. The average equivalent doses calculated for a study using 740 MBq were 4.9, 6.2, 20.7, 34.5 and 57.0 mSv for the liver, intestines, spleen, kidneys and thyroid, respectively, and the effective dose was 6.1 mSv. CONCLUSION: All absorbed doses were comparable to those known from most of the (99m)Tc studies. (99m)Tc-EDDA/HYNIC-E-[c(RGDfK)]2 obtained from kit formulations showed high tumour uptake in patients with malignant lesions, making it a promising imaging radiopharmaceutical for targeting site-specific breast cancer. The results obtained in this study warrant further clinical studies to determine the specificity and sensitivity of (99m)Tc-EDDA/HYNIC-E-[c(RGDfK)]2.