Building a large gene expression-cancer knowledge base with limited human annotations.

Cancer prevention is one of the most pressing challenges that public health needs to face. In this regard, data-driven research is central to assist medical solutions targeting cancer. To fully harness the power of data-driven research, it is imperative to have well-organized machine-readable facts into a knowledge base (KB). Motivated by this urgent need, we introduce the Collaborative Oriented Relation Extraction (CORE) system for building KBs with limited manual annotations. CORE is based on the combination of distant supervision and active learning paradigms and offers a seamless, transparent, modular architecture equipped for large-scale processing. We focus on precision medicine and build the largest KB on 'fine-grained' gene expression-cancer associations-a key to complement and validate experimental data for cancer research. We show the robustness of CORE and discuss the usefulness of the provided KB. Database URL https://zenodo.org/record/7577127.

Development and Evaluation of 99mTc Tricarbonyl Complexes Derived from Flutamide with Affinity for Androgen Receptor.

With the objective to develop a potential 99mTc radiopharmaceutical for imaging the androgen receptor (AR) in prostate cancer, four ligands bearing the same pharmacophore derived from the AR antagonist flutamide were prepared, labeled with 99mTc, and their structures corroborated via comparison with the corresponding stable rhenium analogs. All complexes were obtained with high radiochemical purity. Three of the complexes were highly stable, and, due to their favorable physicochemical properties, were further evaluated using AR-positive and AR-negative cells in culture. All complexes exhibited considerable uptake in AR-positive cells, which could be blocked by an excess of flutamide. The efflux from the cells was moderate. They also showed significantly lower uptakes in AR-negative cells, indicating interactions with the AR receptor. However, the binding affinities were considerably reduced by the coordination to 99mTc, and the complex that exhibited the best biological behavior did not show sufficient specificity towards AR-positive cells.

The mineralocorticoid receptor modulates timing and location of genomic binding by glucocorticoid receptor in response to synthetic glucocorticoids in keratinocytes.

Glucocorticoids (GCs) exert potent antiproliferative and anti-inflammatory properties, explaining their therapeutic efficacy for skin diseases. GCs act by binding to the GC receptor (GR) and the mineralocorticoid receptor (MR), co-expressed in classical and non-classical targets including keratinocytes. Using knockout mice, we previously demonstrated that GR and MR exert essential nonoverlapping functions in skin homeostasis. These closely related receptors may homo- or heterodimerize to regulate transcription, and theoretically bind identical GC-response elements (GRE). We assessed the contribution of MR to GR genomic binding and the transcriptional response to the synthetic GC dexamethasone (Dex) using control (CO) and MR knockout (MREKO ) keratinocytes. GR chromatin immunoprecipitation (ChIP)-seq identified peaks common and unique to both genotypes upon Dex treatment (1 h). GREs, AP-1, TEAD, and p53 motifs were enriched in CO and MREKO peaks. However, GR genomic binding was 35% reduced in MREKO , with significantly decreased GRE enrichment, and reduced nuclear GR. Surface plasmon resonance determined steady state affinity constants, suggesting preferred dimer formation as MR-MR > GR-MR ~ GR-GR; however, kinetic studies demonstrated that GR-containing dimers had the longest lifetimes. Despite GR-binding differences, RNA-seq identified largely similar subsets of differentially expressed genes in both genotypes upon Dex treatment (3 h). However, time-course experiments showed gene-dependent differences in the magnitude of expression, which correlated with earlier and more pronounced GR binding to GRE sites unique to CO including near Nr3c1. Our data show that endogenous MR has an impact on the kinetics and differential genomic binding of GR, affecting the time-course, specificity, and magnitude of GC transcriptional responses in keratinocytes.

Dosis efectivas asociadas a estudios híbridos SPECT-CT en pacientes adultos / Effective dose associated to hybrid SPECT-CT imaging in adult patients / Doses eficazes associadas a estudos de SPECT-CT híbridos em pacientes adultos

Introducción: la técnica de imagen híbrida de SPECT-CT combina la imagen de la tomografía por emisión de fotón único (SPECT) con el estudio de tomografía computada (TC), obteniendo información funcional y anatómica en un mismo estudio. La dosis efectiva total de radiación ionizante recibida en los estudios SPECT-CT puede ser estimada a partir de la dosis efectiva atribuible a la actividad administrada del radiofármaco y la dosis efectiva del componente de tomografía computada (TC). Objetivos: estimar la dosis efectiva total en los protocolos SPECT-CT utilizados en población adulta y determinar el aporte adicional del estudio TC sobre la dosis efectiva total. Método: se evaluaron 258 estudios SPECT-CT para estimar la dosis efectiva total aportada por la administración de los radiofármacos y los estudios de TC de baja dosis. Para estimar el aporte de ambos componentes se utilizaron factores de conversión específicos de cada radiofármaco y región explorada mediante TC. Resultados: la dosis efectiva total (media ± DS) en los estudios SPECT-CT fueron: 12,4 ± 1,44 mSv en el estudio de perfusión miocárdica, 1,14 ± 0,25 mSv en ganglio centinela de mama, 8,6 ± 0,6 mSv paratiroides, 1,48 ± 1,02 mSv tiroides y los estudios óseos de las regiones de cuello 4,5 ± 0,3, tórax 6,07 ± 0,3 mSv, abdomen y pelvis 6,1 ± 0,3 mSv. La dosis de radiación aportada por el estudio TC se encuentra entre 0,46 mSv para la región del tórax en el estudio de ganglio centinela de mama y 2,3 mSv para el SPECT-CT óseo en la región de abdomen y pelvis. Conclusión: se logró estimar la dosis efectiva en los protocolos SPECT-CT de uso clínico más frecuente en población adulta y el aporte de los estudios TC a la dosis efectiva total siendo relativamente baja comparado con la dosis aportada por los radiofármacos administrados con la excepción del estudio de ganglio centinela donde la contribución del componente TC es aproximadamente la mitad de la dosis efectiva total.

Introduction: SPECT-CT Hybrid image technique combines the SPECT (single-photon emission computed tomography) image with the CT (computerized tomography) image to obtain both functional and anatomical images in the same study. The total effective ionizing radiation dose received in SPECT-CT studies may be estimated based on the effective dose from the radiopharmaceutical administered and the effective dose from the CT (computerized tomography) component. Objectives: the study aims to estimate the total effective dose in SPECT-CT protocols applied for the adult population, and to determine the additional contribution from the CT component to the total effective dose. Method: 258 SPECT-CT studies were evaluated to estimate the total effective dose from the administration of radiopharmaceuticals and low dose CT studies. Specific conversion factors for each radiopharmaceutical and area of the body explored with the CT were used to estimate radiation doses from both components. Results: total effective dose (average ± SD) in the SPECT-CT studies was: 12.4 ± 1.44 mSv in the myocardial perfusion study, 1.14 ± 0.25 mSv in the breast sentinel lymph node study, 8.6 ± 0.6 mSv in the parathyroid study, 1.48 ± 1.02 mSv in the thyroid study. As to bone studies, doses found were: 4.5 ± 0.3, in neck studies, 6.07 ± 0.3 mSv in thoracic studies and 6.1 ± 0.3 mSv in abdominal and pelvic studies. The radiation dose from the CT study ranges from 0.46 mSv for the thoracic region on the breast sentinel lymph node study to 2.3 mSv for the bone SPECT-CT study of the abdominal and pelvic region. Conclusions: we managed to estimate the effective dose in the the most frequently used SPECT-CT protocols for the adult population and the contribution of CT studies to the total effective dose. It was found to be relatively low when compared to the dose contributed by the radiopharmaceuticals administered, with the exception of the sentinel lymph node study for which the contribution from the CT study is approximately half the total effective dose.

Introdução: a técnica de imagem híbrida SPECT-CT combina a imagem de tomografia por emissão de fóton único (SPECT) com o estudo de tomografia computadorizada (TC), obtendo informações funcionais e anatômicas no mesmo estudo. A dose efetiva total de radiação ionizante recebida em estudos SPECT-CT pode ser estimada a partir da dose efetiva atribuível à atividade administrada do radiofármaco e da dose efetiva do componente de tomografia computadorizada (TC). Objetivos: estimar a dose efetiva total nos protocolos SPECT-CT utilizados na população adulta e determinar a contribuição adicional do estudo de TC na dose efetiva total. Método : 258 estudos SPECT-CT foram avaliados para estimar a dose efetiva total fornecida pela administração de radiofármacos e estudos de TC de baixa dose. Para estimar a contribuição de ambos os componentes, foram utilizados fatores de conversão específicos para cada radiofármaco e região explorada pela TC. ⁠ Resultados: a dose efetiva total (média ± DP) nos estudos SPECT-CT foi: 12,4 ± 1,44 mSv no estudo de perfusão miocárdica, 1,14 ± 0,25 mSv no linfonodo sentinela mamário, 8,6 ± 0,6 mSv paratireoide, 1,48 ± 1,02 mSv estudos de tireoide e ossos das regiões do pescoço 4,5 ± 0,3, tórax 6,07 ± 0,3 mSv, abdômen e pelve 6,1 ±0,3mSv. A dose de radiação fornecida pelo estudo de TC está entre 0,46 mSv para a região do tórax no estudo do linfonodo sentinela da mama e 2,3 mSv para o SPECT-CT ósseo na região do abdome e pelve. Conclusão: foi possível estimar a dose efetiva nos protocolos de SPECT-CT mais utilizados clinicamente na população adulta e a contribuição dos estudos de TC para a dose efetiva total, sendo relativamente baixa em relação à dose fornecida pelos radiofármacos administrados com a exceção do estudo do linfonodo sentinela onde a contribuição do componente TC é aproximadamente metade da dose efetiva total.

Validation of Convolutional Neural Networks for Fast Determination of Whole-Body Metabolic Tumor Burden in Pediatric Lymphoma.

18F-FDG PET/CT quantification of whole-body tumor burden in lymphoma is not routinely performed because of the lack of fast methods. Although the semiautomatic method is fast, it is not fast enough to quantify tumor burden in daily clinical practice. Our purpose was to evaluate the performance of convolutional neural network (CNN) software in localizing neoplastic lesions in whole-body 18F-FDG PET/CT images of pediatric lymphoma patients. Methods: The retrospective image dataset, derived from the data pool of the International Atomic Energy Agency (coordinated research project E12017), included 102 baseline staging 18F-FDG PET/CT studies of pediatric lymphoma patients (mean age, 11 y). The images were quantified to determine the whole-body tumor burden (whole-body metabolic tumor volume [wbMTV] and whole-body total lesion glycolysis [wbTLG]) using semiautomatic software and CNN-based software. Both were displayed as semiautomatic wbMTV and wbTLG and as CNN wbMTV and wbTLG. The intraclass correlation coefficient (ICC) was applied to evaluate concordance between the CNN-based software and the semiautomatic software. Results: Twenty-six patients were excluded from the analysis because the software was unable to perform calculations for them. In the remaining 76 patients, CNN and semiautomatic wbMTV tumor burden metrics correlated strongly (ICC, 0.993; 95% CI, 0.989 - 0.996; P < 0.0001), as did CNN and semiautomatic wbTLG (ICC, 0.999; 95% CI, 0.998-0.999; P < 0.0001). However, the time spent calculating these metrics was significantly (<0.0001) less by CNN (mean, 19 s; range, 11-50 s) than by the semiautomatic method (mean, 21.6 min; range, 3.2-62.1 min), especially in patients with advanced disease. Conclusion: Determining whole-body tumor burden in pediatric lymphoma patients using CNN is fast and feasible in clinical practice.

Diagnostic Performance and Clinical Impact of 68Ga-PSMA-11 PET/CT Imaging in Early Relapsed Prostate Cancer After Radical Therapy: A Prospective Multicenter Study (IAEA-PSMA Study).

Biochemical recurrence (BCR) is a clinical challenge in prostate cancer (PCa) patients, as recurrence localization guides subsequent therapies. The use of PET with prostate-specific membrane antigen (PSMA) provides better accuracy than conventional imaging practice. This prospective, multicenter, international study was performed to evaluate the diagnostic performance and clinical impact of PSMA PET/CT for evaluating BCR in PCa patients in a worldwide scenario. Methods: Patients were recruited from 17 centers in 15 countries. Inclusion criteria were histopathologically proven prostate adenocarcinoma, previous primary treatment, clinically established BCR, and negative conventional imaging (CT plus bone scintigraphy) and MRI results for patients with PSA levels of 4-10 ng/mL. All patients underwent PET/CT scanning with 68Ga-PSMA-11. Images and data were centrally reviewed. Multivariate logistic regression analysis was applied to identify the independent predictors of PSMA-positive results. Variables were selected for this regression model on the basis of significant associations in the univariate analysis and previous clinical knowledge: Gleason score, the PSA level at the time of the PET scan, PSA doubling time, and primary treatment strategy. All patients were monitored for a minimum of 6 mo. Results: From a total of 1,004 patients, 77.7% were treated initially with radical prostatectomy and 22.3% were treated with radiotherapy. Overall, 65.1% had positive PSMA PET/CT results. PSMA PET/CT positivity was correlated with the Gleason score, PSA level at the time of the PET scan, PSA doubling time, and radiotherapy as the primary treatment (P < 0.001). Treatment was modified on the basis of PSMA PET/CT results in 56.8% of patients. PSMA PET/CT positivity rates were consistent and not statistically different among countries with different incomes. Conclusion: This multicenter, international, prospective trial of PSMA PET/CT confirmed its capability for detecting local and metastatic recurrence in most PCa patients in the setting of BCR. PSMA PET/CT positivity was correlated with the Gleason score, PSA level at the time of the PET scan, PSA doubling time, and radiotherapy as the primary treatment. PSMA PET/CT results led to changes in therapeutic management in more than half of the cohort. The study demonstrated the reliability and worldwide feasibility of PSMA PET/CT in the workup of PCa patients with BCR.

Nuclear Medicine Departments in the Era of COVID-19.

From the outset of the COVID-19 pandemic we, the nuclear medicine (NM) community, expediently mobilized to enable continuity of essential services to the best of our abilities. For example, we effectuated adapted guidelines for NM standard operating procedures (SOPs) and enacted heightened infection protection measures for staff, patients, and the public, alike. Challenges in radionuclide supply chains were identified and often met. NM procedural volumes declined globally and underwent restoration of varying degrees, contingent upon local contexts. Serial surveys have gauged and chronicled such geographical variance of the impact of COVID-19 on NM service delivery and, though it may be too early to fully understand the long-term consequences of reduced NM services, overall, we can certainly expect that this era adversely affected the management of many patients afflicted with non-communicable diseases. Today we are unquestionably better prepared to face unforeseen outbreaks, but a degree of uncertainty lingers. Which lessons learned will endure in the form of permanent NM pandemic preparedness procedures and protocols? In this spirit, the present manuscript presents a revision of prior recommendations issued mid-pandemic to NM centers, some of which may become mainstays in NM service delivery and implementation. Discussed herein are (1) comparative worldwide survey results of the measurable impact of COVID-19 on the practice of nuclear medicine (2) the definitions of a pandemic and its phases (3) relevant, recently developed or updated guidelines specific to nuclear medicine (4) incidental findings of COVID-19 on hybrid nuclear medicine studies performed primarily for oncologic indications and (5) how pertinent pedagogical methods for medical education, research, and development have been re-invented in a suddenly more virtual world. NM professionals shall indefinitely adopt many of the measures implemented during this pandemic, to enable continuity of essential services while preventing the spread of the virus. Which ones? Practices must remain ready for possible new peaks or variants of the roiling COVID-19 contagion and for the emergence of potential new pathogens that may incite future outbreaks or pandemics. Communications technologies are here to stay and will continue to be used in a broad spectrum of applications, from telemedicine to education, but how best? NM departments must align synergistically with these trends, considering what adaptations to a more virtual professional environment should not only last but be further innovated. The paper aims to provide recent history, analysis, and a springboard for continued constructive dialogue. To best navigate the future, NM must continue to learn from this crisis and must continue to bring new questions, evidence, ideas, and warranted systematic updates to the figurative table.

18F-fallypride and 11C-methionine positron emission tomography/computed tomography for the study of prolactinomas and nonfunctioning pituitary adenomas: A case series.

Some studies have assessed the expression of dopaminergic dopamine 2 (D2)/3 receptors in prolactinomas and nonfunctioning pituitary adenomas (NFPA) by positron emission tomography/computed tomography (PET/CT) with 11C-raclopride, proving that this modality can be useful to predict the response to treatment with dopamine agonists. However, the use of 11C-labeled radiotracers is limited, as it requires a cyclotron in the PET center. 18F-fallypride is a radiotracer that has proven useful in assessing the expression of D2/3 receptors. As it is labeled with 18F, it can be produced and transported to distant PET centers. There are no studies on the usefulness of 18F-fallypride for the evaluation of patients with prolactinomas and NFPA. The aim of this study was to describe the first case series of patients with prolactinomas and NFPA studied with 18F-fallypride and 11C-methionine PET/CT to reveal D2/3 expression and amino acid (AA) metabolism. 18F-fallypride and 11C-methionine uptake were assessed in a case series of six patients, five with prolactinomas and one with a NFPA, and compared with clinical presentation and follow-up at 6-18 months. All patients presented with macroadenomas, with a wide range of AA metabolism, as revealed by 11C-methionine PET/CT. 18F-fallypride PET/CT identified low to moderate/high D2/3 expression in the tumors. The patient that presented low expression of D2/3 in the tumor and high AA metabolism showed a poor response to DA therapy. 18F-fallypride was able to reveal D2/3 receptor expression in prolactinomas and NFPA, with the advantage of been a more accessible radiotracer in comparison with previous 11C labeled analogs.

Clinical Impact of PET With 18F-FDG and 11C-PIB in Patients With Dementia in a Developing Country.

Introduction: The objective of this study was to evaluate the clinical impact PET with 18F-FDG and 11C-PIB in patients with dementia in a developing country. Methodology: Retrospective study of the patients referred for the evaluation of dementia to the only PET center in Uruguay. A total of 248 patients were identified, from which 70 patients were included based on the availability of medical history and clinical follow-up. Main outcomes included change in diagnosis, diagnostic dilemma and AD treatment. We evaluated the association of clinical outcomes with PET concordance with baseline diagnosis, diagnostic dilemma, level of education, AD pathology/Non-AD pathology (AD/Non-AD), baseline diagnosis and 11C-PIB PET result. Results: Baseline clinical diagnosis was concordant with 18F-FDG and 11C-PIB PET results in 64.7 and 77.1% of the patients, respectively. Change in diagnosis after PET was identified in 30.0% of the patients and was associated with discordant 18F-FDG (p = 0.002) and 11C-PIB (p < 0.001) PET results, previous diagnostic dilemma (p = 0.005), low education (p = 0.027), Non-AD baseline diagnosis (p = 0.027), and negative 11C-PIB PET result (p < 0.001). Only the last variable remained significant in the multivariate analysis (adjusted p = 0.038). Diagnostic dilemma decreased after PET from 15.7 to 7.1% (p = 0.11) and was associated with Non-AD diagnosis (p = 0.002) and negative 11C-PIB PET result (p = 0.003). Change in AD treatment after PET occurred in 45.7% of the patients. Conclusion: 18F-FDG and 11C-PIB PET had a significant clinical impact in terms of change in diagnosis and treatment in patients with dementia in a developing country, similar to that reported in high-income countries.

Prognostic value of imaging markers from 18FDG-PET/CT in paediatric patients with Hodgkin lymphoma.

OBJECTIVE: Identification of imaging prognostic parameters for early therapy personalisation to reduce treatment-related morbidity in paediatric Hodgkin lymphoma (HL). Our aim was to evaluate quantitative markers from baseline 2-[18F]fluoro-2-deoxy-d-glucose PET/CT as prognostic factors for treatment outcomes. Another goal was assessing the prognostic value of Deauville score at interim PET/CT. METHODS: Twenty-one patients were prospectively enrolled. Median age was 12 years (range 6-17); 13 were female. Patients underwent PET/CT for disease staging (bPET), at the end of two cycles of chemotherapy (iPET) and after chemotherapy. A total of 173 lesions were segmented from bPET. We calculated 51 texture features for each lesion. Total metabolic tumour volume and total lesion glycolysis from bPET were calculated for response prediction at iPET. Univariate and multivariate analyses were used for optimal cut-off values to separate responders at iPET according to the Deauville score. RESULTS: We identified four texture features as possible independent predictors of treatment outcomes at iPET. The areas under the ROC for univariate analysis were 0.89 (95% CI, 0.75-1), 0.82 (95% CI, 0.64-1), 0.79 (95% CI, 0.59-0.99) and 0.89 (95% CI, 0.75-1). The survival curves for patients assigned Deauville scores 1, 2, 3 and X were different from those assigned a score 4, with 4-year progression free-survival (PFS) rates of 85 versus 29%, respectively (P = 0.05). CONCLUSIONS: We found four textural features as candidates for predicting early response to chemotherapy in paediatric patients with HL. The Deauville score at iPET was useful for differentiating PFS rates.

Quantitative comparison between single-photon emission computed tomography and positron emission tomography imaging of lung ventilation with 99mTc-technegas and 68Ga-gallgas in patients with chronic obstructive pulmonary disease: A pilot study.

The aim of this study was quantitative comparison between 68Ga-Gallgas positron emission tomography (PET) and 99mTc-Technegas single photon emission computed tomography (SPECT) for lung ventilation function assessment in patients with moderate-to-severe obstructive pulmonary disease and to identify image-derived texture features correlating to the physiologic parameters. Five patients with moderate-to-severe chronic obstructive pulmonary disease with PET and SPECT lung ventilation scans were selected for this study. Threshold-based segmentations were used to compare ventilated regions between both imaging techniques. Histograms of both scans were compared to reveal main differences in distributions of radiotracers. Volumes of segmentation as well as 50 textural features measured in the pulmonary region were correlated to the forced expiratory volume in 1 s (FEV1) as the relevant physiological variable. A better peripheral distribution of the radiotracer was observed in PET scans for three out of five patients. A segmentation threshold of 27% and 31% for normalized scans, for PET and SPECT respectively, was found optimal for volume correlation with FEV1. A high correlation (Pearson correlation coefficient >0.9) was found between 16 texture features measured from SPECT and 7 features measured from PET and FEV1. Quantitative measurements revealed different tracer distribution in both techniques. These results suggest that tracer distribution patterns may depend on the cause of the pulmonary obstruction. We found several texture features measured from SPECT to correlate to FEV1.

Hallazgo de Tumor Maligno/Premaligno Insospechado en Estudios 18 F-FDG PET/TC en Pacientes Oncológicos: Incidental Malignant/Premalignant Tumor Detection in Oncological Patients / 18 f-fdg pet/ct

Objetivo Determinar la frecuencia y el tipo de tumor maligno/premaligno insospechado como hallazgo en estudios 18 F-FDG PET/TC en pacientes oncológicos. Material y Métodos Se revisaron retrospectivamente (de enero de 2014 a marzo de 2017), informes de estudios 18 F-FDG PET/TC de pacientes oncológicos, identificando aquellos pacientes con hallazgo de lesión sospechosa de otro tumor maligno como hallazgo incidental. La información fue obtenida a partir de determinadas "palabras clave" en la base de datos del Centro. Los hallazgos se confirmaron mediante histopatología y/o seguimiento clínico y paraclínico de como mínimo seis meses. Resultados De 4.086 pacientes oncológicos estudiados con 18 F-FDG PET/TC, se encontró lesión sospechosa de otro tumor maligno en 130 (3,2%), de los cuales 72 eran mujeres y 58 hombres, con edad media de 61 años. Los tumores primarios más frecuentes (aquellos que motivaron el pedido del examen PET/CT inicialmente), fueron de mama (n = 27), pulmón (n = 27) y colo-recto (n = 20). Se confirmaron por histopatología 49 (1,2%) nuevos tumores malignos/premalignos y dos lesiones metastásicas. La localización del segundo tumor primario correspondió a: colon (n = 18), pulmón (n = 6), mama (n = 6), linfoma (n = 3), ovario (n = 2), endometrio/cuello uterino (n = 2), tiroides (n = 2) y otros (n = 10). Resultaron 28 hallazgos falsos positivos, 31 pacientes no se estudiaron por progresión lesional y 20 pacientes se perdieron de seguimiento. Discusión La prevalencia de neoplasia primaria maligna múltiple (NPMM) es variable entre 0,7 y 11,7%. En nuestra serie, se encontró lesión sospechosa de segundo tumor en 130 casos (3,2%), de los cuales se confirmaron 49 segundos tumores (1,2%), similar a Conclusiones La tasa de detección de tumor maligno insospechado confirmado histológicamente fue de 1,2%. Todo hallazgo incidental sospechoso de malignidad en 18 F-FDG PET/TC debe ser estudiado, ya que puede corresponder a un segundo tumor maligno no sospechado con posibilidad de tratamiento curativo.

Purpose To determine the frequency and type of unexpected malignant/ premalignant tumor as a finding in 18 F-FDG PET/CT studies in oncological patients. Material and Methods Reports of 18 F-FDG PET/CT studies of oncological patients were reviewed retrospectively (from January 2014 to March 2017), with the finding of suspicious lesion of another malignant tumor. The information was obtained from certain "keywords" in the Center's database. The findings were confirmed by histopathology when possible and with clinical and paraclinical follow-up for at least six months. Results Of 4086 oncological patients, studied with 18 F-FDG PET/CT, a suspicious lesion of another malignant tumor was found in 130 (3.2%), 72 female and 58 male sex, average age 61 years. The most frequent primary tumors were: breast (n = 27), lung (n = 27) and colo-rectum (n = 20). 49 (1.2%) new malignant/premalignant tumors and two metastatic lesions were confirmed by histopathology. The location of the second primary tumor was: colon (n = 18), lung (n = 6), breast (n = 6), lymphoma (n = 3), ovary (n = 2), endometrium/cervix (n = 2), thyroid (n = 2) and others (n = 10). There were 28 false positive findings, 31 patients were not studied for progression and 20 patients were lost to follow-up. Discussion The prevalence of multiple malignant primary neoplasia (MMPN) is variable between 0.7 and 11.7%. In our series, a suspicious second tumor lesion was found in 130 cases (3.2%), of which 49 second tumors (1.2%) were confirmed, similar to that reported by other authors. Conclusions The detection rate of unsuspected malignant tumor was 1.2%, coincident with the literature. Any incidental finding suspicious of malignancy in 18 F-FDG PET/CT should be studied since in most cases it corresponds to early diagnosis with the possibility of curative treatment.

Is True Whole-Body 18F-FDG PET/CT Required in Pediatric Lymphoma? An IAEA Multicenter Prospective Study.

Guidelines recommend true whole-body 18F-FDG PET/CT scans from vertex to toes in pediatric lymphoma patients, although this suggestion has not been validated in large clinical trials. The objective of the study was to evaluate the incidence and clinical impact of lesions outside the "eyes to thighs" regular field of view (R-FOV) in 18F-FDG PET/CT staging (sPET) and interim (iPET) scans in pediatric lymphoma patients. Methods: True whole-body sPET and iPET scans were prospectively obtained in pediatric lymphoma patients (11 worldwide centers). Expert panel central review of sPET and iPET scans were evaluated for lymphoma lesions outside the R-FOV and clinical relevance of these findings. Results: A total of 610 scans were obtained in 305 patients. The sPET scans did not show lesions outside the R-FOV in 91.8% of the patients, whereas in 8.2% patients the sPET scans demonstrated lesions also outside the R-FOV (soft tissue, bone, bone marrow, and skin); however, the presence of these lesions did not change the clinical stage of any patient and did not affect treatment decision. Among the 305 iPET scans, there were no new positive 18F-FDG-avid lesions outside the R-FOV, when compared with their paired sPET scans. A single lesion outside the R-FOV on iPET occurred in 1 patient (0.3%), with the primary lesion diagnosed in the femur on sPET that persisted on iPET. Conclusion: The identification of additional lesions outside the R-FOV (eyes to thighs) using 18F-FDG PET/CT has no impact in the definition of the clinical stage of disease and minimal impact in the treatment definition of patients with pediatric lymphoma. As so, R-FOV for both sPET and iPET scans could be performed.

68Ga-PSMA and 11C-Choline comparison using a tri-modality PET/CT-MRI (3.0 T) system with a dedicated shuttle.

BACKGROUND: The aim of this study was to prospectively compare the detection rate of 68Ga-PSMA versus 11C-Choline in men with prostate cancer with biochemical recurrence and to demonstrate the added value of a tri-modality PET/CT-MRI system. METHODS: We analysed 36 patients who underwent both 11C-Choline PET/CT and 68Ga-PSMA PET/CT scanning within a time window of 1-2 weeks. Additionally, for the 68Ga-PSMA scan, we used a PET/CT-MRI (3.0 T) system with a dedicated shuttle, acquiring MRI images of the pelvis. RESULTS: Both scans were positive in 18 patients (50%) and negative in 8 patients (22%). Nine patients were positive with 68Ga-PSMA alone (25%) and one with 11C-Choline only (3%). The median detected lesion per patient was 2 for 68Ga-PSMA (range 0-93) and 1 for 11C-Choline (range 0-57). Tumour to background ratios in all concordant lesions (n = 96) were higher for 68Ga-PSMA than for 11C-Choline (110.3 ± 107.8 and 27.5 ± 17.1, mean ± S.D., for each tracer, respectively P = 0.0001). The number of detected lesions per patient was higher for 11C-Choline in those with PSA ≥ 3.3 ng/mL, while the number of detected lesions was independent of PSA levels for 68Ga-PSMA using the same PSA cut-off value. Metastatic pelvic lesions were found in 25 patients (69%) with 68Ga-PSMA PET/CT, in 18 (50%) with 11C-Choline PET/CT and in 21 (58%) with MRI (3.0 T). MRI was very useful in detecting recurrence in cases classified as indeterminate by means of PET/CT alone at prostate bed. CONCLUSIONS: In patients with prostate cancer with biochemical recurrence 68Ga-PSMA detected more lesions per patient than 11C-Choline, regardless of PSA levels. PET/CT-MRI (3.0 T) system is a feasible imaging modality that potentially adds useful relevant information with increased accuracy of diagnosis.

Dose-dependent selection drives lineage replacement during the experimental evolution of SDHI fungicide resistance in Zymoseptoria tritici.

Fungicide resistance is a constant threat to agricultural production worldwide. Molecular mechanisms of fungicide resistance have been studied extensively in the wheat pathogen Zymoseptoria tritici. However, less is known about the evolutionary processes driving resistance development. In vitro evolutionary studies give the opportunity to investigate this. Here, we examine the adaptation of Z. tritici to fluxapyroxad, a succinate dehydrogenase (Sdh) inhibitor. Replicate populations of Z. tritici derived from the sensitive isolate IPO323 were exposed to increasing concentrations of fluxapyroxad with or without UV mutagenesis. After ten increases in fungicide concentration, sensitivity had decreased dramatically, with replicate populations showing similar phenotypic trajectories. Sequencing the Sdh subunit B, C, and D encoding genes identified seven mutations associated with resistance to fluxapyroxad. Mutation frequency over time was measured with a pyrosequencing assay, revealing sequential lineage replacement in the UV-mutagenized populations but not in the untreated populations. Repeating selection from set time-points with different fungicide concentrations revealed that haplotype replacement of Sdh variants was driven by dose-dependent selection as fungicide concentration changed, and was not mutation-limited. These findings suggest that fungicide field applications may select for highly insensitive Sdh variants with higher resistance factors if the fungicide concentration is increased to achieve a better disease control. However, in the absence or presence of lower fungicide concentrations, the spread of these strains might be restricted if the underlying Sdh mutations carry fitness penalties.

Early Detection of Bone Metastasis in Small Cell Neuroendocrine Carcinoma of the Cervix by 68Ga-DOTATATE PET/CT Imaging.

The neuroendocrine small cell carcinoma of the cervix is a rare malignancy that has a poor prognosis due to early lymphatic and hematogenous spread. We herein report a case of a 27- year-old woman who was referred for initial staging of a neuroendocrine small cell carcinoma with previous unremarkable structural imaging. Ga-DOTATATE PET/CT revealed focal uptake at the primary tumor and in a solitary pelvic bone lesion suggestive of metastases that was further confirmed by CT-guided biopsy. Somatostatin receptor PET/CT may be a useful image modality for early detection of metastases to guide treatment in these patients.

177Lu-DOTA-Bevacizumab: Radioimmunotherapy Agent for Melanoma.

BACKGROUND: Vascular endothelial growth factor (VEGF) is one of the classic factors to tumor-induced angiogenesis in several types, including melanoma. Bevacizumab is a humanized monoclonal antibody directed against VEGF. OBJECTIVE: To radiolabel Bevacizumab with 177-Lutetium as a potential radioimmunotherapy agent for melanoma. METHODS: Bevacizumab was derivatized with DOTA-NHS-ester at 4 ºC for 18 h. DOTABevacizumab was radiolabeled with 177LuCl3 (15 MBq/mg) at 37 ºC for 1 h. The studies were performed in healthy and B16F1 tumor-bearing C57BL/6J mice at 24 and 48 h (n = 5). Scinthigraphic imaging studies were performed at 24 h to determine the radiochemical stability, targeting specificity and pharmacokinetics of the 177Lutetium-labeled antibody. RESULTS: DOTA-Bevacizumab was efficiently labeled with 177LuCl3 at 37 °C. The in-vitro stability of labeled product was optimal over 72 h. In-vivo biodistribution studies showed a high liver and tumor uptake of 177Lu-DOTA-Bevacizumab, with tumor-to-muscle ratios of 11.58 and 6.37 at 24 and 48 h p.i. Scintigraphic imaging of melanoma tumor-bearing C57BL/6J mice showed liver and a high tumor selective uptake of 177Lu-DOTA-Bevacizumab at 24 h. CONCLUSIONS: Our results support the potential role of 177Lu-DOTA-Bevacizumab as a novel radioimmunotherapy agent for melanoma. We hope that these novel molecular imaging agents will open the path to new diagnostic and therapeutic strategies for Melanoma disease.

Fab(nimotuzumab)-HYNIC-99mTc: Antibody Fragmentation for Molecular Imaging Agents.

Finally, fast blood clearance nimotuzumab is a humanized monoclonal antibody that recognise, with high specific affinity, the epidermal growth factor receptor (EGF-R) which play an important role in the growth process associated with many solid tumors. In this work, the whole antibody was digested with papain in order to generate a Fab fragment, derivatized with NHS-HYNIC-Tfa and radiolabel with technetium-99m (99mTc) as a potential agent of molecular imaging of cancer. Both, whole and fragment radiolabels were in-vivo and in-vitro characterized. Radiolabeling conditions with Tricine as coligand and quality controls were assessed to confirm the integrity of the labeled fragment. Biodistribution and imaging studies in normal and spontaneous adenocarcinoma mice were performed at different times to determine the in-vivo characteristics of the radiolabel fragment. Tumor localization was visualized by conventional gamma camera imaging studies, and the results were compared with the whole antibody. Also, an immunoreactivity assay was carried out for both. The results showed clearly the integrity of the nimotuzumab fragment and the affinity by the receptor was verified. Fab(nimotuzumab)-HYNIC was obtained with high purity and a simple strategy of radiolabeling was performed. Finally, a fast blood clearance was observed in the biodistribution studies increasing the tumor uptake of Fab(nimotuzumab)- HYNIC-99mTc over time, with tumor/muscle ratios of 3.81 ± 0.50, 5.16 ± 1.97 and 6.32 ± 1.98 at 1 h, 4 h and 24 h post injection. Urinary excretion resulted in 32.89 ± 3.91 %ID eliminated at 24 h. Scintigraphy images showed uptake in the tumor and the activity in non-target organs was consistent with the biodistribution data at the same time points. Hence, these preliminary results showed important further characteristic of Fab(nimotuzumab)-HYNIC-99mTc as a molecular imaging agent of cancer.

New Exercise-Dipyridamole Combined Test for Nuclear Cardiology in Insufficient Effort: Appropriate Diagnostic Sensitivity Keeping Exercise Prognosis / Novo Teste Combinado Exercício-Dipiridamol para Cardiologia Nuclear no Esforço Insuficiente: Adequada Sensibilidade Diagnóstica Mantendo Prognóstico do Exercício

AbstractBackground:Myocardial perfusion scintigraphy (MPS) in patients not reaching 85% of the maximum predicted heart rate (MPHR) has reduced sensitivity.Objectives:In an attempt to maintain diagnostic sensitivity without losing functional exercise data, a new exercise and dipyridamole combined protocol (EDCP) was developed. Our aim was to evaluate the feasibility and safety of this protocol and to compare its diagnostic sensitivity against standard exercise and dipyridamole protocols.Methods:In patients not reaching a sufficient exercise (SE) test and with no contraindications, 0.56 mg/kg of dipyridamole were IV administered over 1 minute simultaneously with exercise, followed by 99mTc-MIBI injection.Results:Of 155 patients, 41 had MPS with EDCP, 47 had a SE test (≥ 85% MPHR) and 67 underwent the dipyridamole alone test (DIP). They all underwent coronary angiography within 3 months. The three stress methods for diagnosis of coronary lesions had their sensitivity compared. For stenosis ≥ 70%, EDCP yielded 97% sensitivity, SE 90% and DIP 95% (p = 0.43). For lesions ≥ 50%, the sensitivities were 94%, 88% and 95%, respectively (p = 0.35). Side effects of EDCP were present in only 12% of the patients, significantly less than with DIP (p < 0.001).Conclusions:The proposed combined protocol is a valid and safe method that yields adequate diagnostic sensitivity, keeping exercise prognostic information in patients unable to reach target heart rate, with fewer side effects than the DIP.

ResumoFundamento:A cintilografia de perfusão miocárdica (CPM) em pacientes que não alcançam 85% da frequência cardíaca máxima prevista (FCMP) no teste de esforço apresenta reduzida sensibilidade.Objetivos:Na tentativa de manter a sensibilidade diagnóstica sem perder os dados funcionais ergométricos, desenvolveu‑se um novo protocolo combinado de exercício e dipiridamol (PCED). O objetivo deste estudo foi avaliar a viabilidade e segurança desse protocolo e comparar sua sensibilidade diagnóstica com os de protocolos convencionais de exercício e dipiridamol.Métodos:Pacientes que não atingiram um teste de esforço suficiente (TES) e sem contraindicações receberam por via intravenosa 0,56 mg/kg de dipiridamol por 1 minuto ao mesmo tempo em que se exercitavam. Seguiu-se injeção de99mTc-metoxi-isobutil-isonitrila.Resultados:Dos 155 pacientes incluídos, 41 foram submetidos a CPM com PCED, 47 a TES (≥ 85% FCMP) e 67 ao teste convencional apenas com dipiridamol (DIP). Todos foram submetidos a coronariografia até três meses depois. Compararam-se as sensibilidades dos três métodos para diagnosticar lesões coronarianas. Para estenose ≥ 70%, as sensibilidades foram: no PCED 97%; no TES, 90%; e no DIP, 95% (p = 0,43). Para lesões ≥ 50%, as sensibilidades foram 94%, 88% e 95%, respectivamente (p = 0,35). Efeitos colaterais foram observados em apenas 12% dos pacientes submetidos ao PCED, significativamente menos do que no DIP (p < 0,001).Conclusões:O PCED é um método válido e seguro, com adequada sensibilidade diagnóstica, que mantém a informação prognóstica do teste de esforço nos pacientes que não conseguem atingir a frequência cardíaca alvo, com menos efeitos colaterais do que o DIP.

New exercise-dipyridamole combined test for nuclear cardiology in insufficient effort: appropriate diagnostic sensitivity keeping exercise prognosis.

BACKGROUND: Myocardial perfusion scintigraphy (MPS) in patients not reaching 85% of the maximum predicted heart rate (MPHR) has reduced sensitivity. OBJECTIVES: In an attempt to maintain diagnostic sensitivity without losing functional exercise data, a new exercise and dipyridamole combined protocol (EDCP) was developed. Our aim was to evaluate the feasibility and safety of this protocol and to compare its diagnostic sensitivity against standard exercise and dipyridamole protocols. METHODS: In patients not reaching a sufficient exercise (SE) test and with no contraindications, 0.56 mg/kg of dipyridamole were IV administered over 1 minute simultaneously with exercise, followed by 99mTc-MIBI injection. RESULTS: Of 155 patients, 41 had MPS with EDCP, 47 had a SE test (≥ 85% MPHR) and 67 underwent the dipyridamole alone test (DIP). They all underwent coronary angiography within 3 months. The three stress methods for diagnosis of coronary lesions had their sensitivity compared. For stenosis ≥ 70%, EDCP yielded 97% sensitivity, SE 90% and DIP 95% (p = 0.43). For lesions ≥ 50%, the sensitivities were 94%, 88% and 95%, respectively (p = 0.35). Side effects of EDCP were present in only 12% of the patients, significantly less than with DIP (p < 0.001). CONCLUSIONS: The proposed combined protocol is a valid and safe method that yields adequate diagnostic sensitivity, keeping exercise prognostic information in patients unable to reach target heart rate, with fewer side effects than the DIP.