Insulinoma maligno: PET/TC con 18F-DOPA y 68Ga-DOTATATE y tratamiento con 177Lu-DOTATATE / Malignant insulinoma: 18F-DOPA and 68Ga-DOTATATE PET/CT and treatment with 177Lu-DOTATATE

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Human Asymptomatic Epitope Peptide/CXCL10-Based Prime/Pull Vaccine Induces Herpes Simplex Virus-Specific Gamma Interferon-Positive CD107+ CD8+ T Cells That Infiltrate the Corneas and Trigeminal Ganglia of Humanized HLA Transgenic Rabbits and Protect against Ocular Herpes Challenge.

Herpes simplex virus 1 (HSV-1) is a prevalent human pathogen that infects the cornea, causing potentially blinding herpetic disease. A clinical herpes vaccine is still lacking. In the present study, a novel prime/pull vaccine was tested in a human leukocyte antigen (HLA) transgenic rabbit model of ocular herpes (HLA Tg rabbits). Three peptide epitopes were selected, from the HSV-1 membrane glycoprotein C (UL44400-408), the DNA replication binding helicase (UL9196-204), and the tegument protein (UL25572-580), all preferentially recognized by CD8+ T cells from "naturally protected" HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who never had recurrent corneal herpetic disease). HLA Tg rabbits were immunized with a mixture of these three ASYMP CD8+ T cell peptide epitopes (UL44400-408, UL9196-204, and UL25572-580), which were delivered subcutaneously with CpG2007 adjuvant (prime). Fifteen days later, half of the rabbits received a topical ocular treatment with a recombinant neurotropic adeno-associated virus type 8 (AAV8) vector expressing the T cell-attracting CXCL10 chemokine (pull). The frequency and function of HSV-specific CD8+ T cells induced by the prime/pull vaccine were assessed in the peripheral blood, cornea, and trigeminal ganglion (TG). Compared to the cells generated in response to peptide immunization alone, the peptide/CXCL10 prime/pull vaccine generated frequent polyfunctional gamma interferon-positive (IFN-γ+) CD107+ CD8+ T cells that infiltrated both the cornea and TG. CD8+ T cell mobilization into the cornea and TG of prime/pull-vaccinated rabbits was associated with a significant reduction in corneal herpesvirus infection and disease following an ocular HSV-1 (strain McKrae) challenge. These findings draw attention to the novel prime/pull vaccine strategy for mobilizing antiviral CD8+ T cells into tissues to protect against herpesvirus infection and disease.IMPORTANCE There is an urgent need for a vaccine against widespread herpes simplex virus infections. The present study demonstrates that immunization of HLA transgenic rabbits with a peptide/CXCL10 prime/pull vaccine triggered mobilization of HSV-specific CD8+ T cells locally into the cornea and TG, the sites of acute and latent herpesvirus infections, respectively. Mobilization of antiviral CD8+ T cells into the cornea and TG of rabbits that received the prime/pull vaccine was associated with protection against ocular herpesvirus infection and disease following an ocular HSV-1 challenge. These results highlight the importance of the prime/pull vaccine strategy to bolster the number and function of protective CD8+ T cells within infected tissues.

Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8+ T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease.

Recurrent viral diseases often occur after the viruses evade the hosts' immune system, by inducing exhaustion of antiviral T cells. In the present study, we found that functionally exhausted herpes simplex virus type 1 (HSV-1) -specific CD8+ T cells, with elevated expression of lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor that promotes T cell exhaustion, were frequent in symptomatic (SYMP) patients with a history of numerous episodes of recurrent corneal herpetic disease. Similarly, following UV-B induced virus reactivation from latency the symptomatic wild-type (WT) B6 mice that developed increase virus shedding and severe recurrent corneal herpetic disease had more exhausted HSV-specific LAG-3+CD8+ T cells in both trigeminal ganglia (TG) and cornea. Moreover, a therapeutic blockade of LAG-3 immune checkpoint with antagonist antibodies combined with a therapeutic immunization with gB498-505 peptide immunodominant epitope of latently infected B6 mice significantly restored the quality and quantity of functional HSV-1 gB498-505 specific CD8+ T cells in both TG and cornea and protected against UV-B induced recurrent corneal herpes infection and disease. In contrast to dysfunctional HSV-specific CD8+ T cells from WT B6 mice, more functional HSV-specific CD8+ T cells were detected in LAG-3-/- deficient mice and were associated with less UV-B induced recurrent corneal herpetic disease. Thus, the LAG-3 pathway plays a fundamental role in ocular herpes T cell immunopathology and provides an important immune checkpoint target that can synergizes with T cell-based therapeutic vaccines against symptomatic recurrent ocular herpes.

Accuracy of FDG-PET/CT and paraneoplastic antibodies in diagnosing cancer in paraneoplastic neurological syndromes / Utilidad de la PET/TC con FDG y los anticuerpos paraneoplásicos para el diagnóstico de neoplasia en el síndrome neurológico paraneoplásico

Objective. There is still no consensus about whether to perform PET/CT to detect carcinoma in paraneoplastic neurological syndromes (PNS) in patients with or without antibodies. The aim of this study is to determine the diagnostic accuracy of PET/CT and antibodies in patients with PNS. Material and Methods. A retrospective study was conducted on patients with clinically suspected PNS between 2008 and 2013. The association between histopathological findings, paraneoplastic antibodies, and PET/CT findings were evaluated. Sensitivity and specificity for the detection of underlying malignancy were calculated for PET/CT and paraneoplastic antibodies. Results. A total of 42 patients were analyzed. Of these 42 patients, 32 (75%) had a classical PNS, 6 (14%) had positive PET/CT findings, and 34 were tested for the presence of antibodies (anti-Hu Ab, anti-Yo Ab, and anti-Ri Ab). Twenty one of 34 patients had positive antibodies. Of the 6 patients with positive PET/CT findings, 6 had positive histopathological results. Among 21 patients with positive biomarkers, carcinoma was confirmed only in 5 patients. One patient with negative antibodies, but positive PET/CT findings, was diagnosed with a tumor. Gastric carcinoma was detected in 1 patient with negative PET/CT findings and antibodies during follow-up. Based on the results, PET/CT was found to have 85.71% sensitivity, 100% specificity, 100% positive and 97.22% negative predictive values in the detection of tumors. Conclusion. PET/CT has a certain diagnostic accuracy for detecting underlying malignancy in patients with PNS, regardless of the presence of paraneoplastic antibodies (AU)

Objetivo. No hay un criterio unánime para realizar PET/TC en la detección de carcinoma en pacientes de síndrome neurológico paraneoplásico (PNS), con o sin anticuerpos. Nuestro objetivo es buscar la utilidad diagnóstica de la PET/TC y los anticuerpos en pacientes con PNS. Material y métodos. Se examinaron retrospectivamente los pacientes con sospecha clínica de PNS estudiados entre 2008 y 2013. Se evaluó la asociación entre los resultados histopatológicos, los anticuerpos y los resultados de la PET/TC. Se calcularon la sensibilidad y la especificidad de la PET/TC y de los anticuerpos paraneoplásicos para la detección de malignidad. Resultados. Se analizaron un total de 42 pacientes. De ellos 32 pacientes (el 75%) tenían un PNS clásico. A todos se les había realizado PET/TC y 6 (el 14%) tuvieron resultados positivos. Se determinó la presencia de anticuerpos en 34 pacientes (anticuerpos anti-Hu, anticuerpos anti-Yo y anticuerpos anti-Ri). Veintiuno de los cuales dieron positivo. Los 6 pacientes con resultados PET/TC positivos tuvieron resultados histopatológicos positivos. Entre los 21 pacientes con biomarcadores positivos, el carcinoma se confirmó solo en 5 pacientes. A un paciente con resultado negativo para anticuerpos, pero positivo en la PET/TC, se le diagnosticó un tumor. Se detectó carcinoma gástrico en un paciente con resultados negativos en la PET/TC y anticuerpos en el periodo de seguimiento. Según los resultados, se comprobó que la PET/TC tiene un 85,71% de sensibilidad, un 100% de especificidad, con valor predictivo positivo de 100% y valor predictivo negativo de 97,22% en la detección de tumores. Conclusión. La PET/TC tiene un cierto grado de exactitud diagnóstica para detectar malignidad subyacente en pacientes con PNS, sin importar la presencia de anticuerpos paraneoplásicos (AU)

Accuracy of FDG-PET/CT and paraneoplastic antibodies in diagnosing cancer in paraneoplastic neurological syndromes.

OBJECTIVE: There is still no consensus about whether to perform PET/CT to detect carcinoma in paraneoplastic neurological syndromes (PNS) in patients with or without antibodies. The aim of this study is to determine the diagnostic accuracy of PET/CT and antibodies in patients with PNS. MATERIAL AND METHODS: A retrospective study was conducted on patients with clinically suspected PNS between 2008 and 2013. The association between histopathological findings, paraneoplastic antibodies, and PET/CT findings were evaluated. Sensitivity and specificity for the detection of underlying malignancy were calculated for PET/CT and paraneoplastic antibodies. RESULTS: A total of 42 patients were analyzed. Of these 42 patients, 32 (75%) had a classical PNS, 6 (14%) had positive PET/CT findings, and 34 were tested for the presence of antibodies (anti-Hu Ab, anti-Yo Ab, and anti-Ri Ab). Twenty one of 34 patients had positive antibodies. Of the 6 patients with positive PET/CT findings, 6 had positive histopathological results. Among 21 patients with positive biomarkers, carcinoma was confirmed only in 5 patients. One patient with negative antibodies, but positive PET/CT findings, was diagnosed with a tumor. Gastric carcinoma was detected in 1 patient with negative PET/CT findings and antibodies during follow-up. Based on the results, PET/CT was found to have 85.71% sensitivity, 100% specificity, 100% positive and 97.22% negative predictive values in the detection of tumors. CONCLUSION: PET/CT has a certain diagnostic accuracy for detecting underlying malignancy in patients with PNS, regardless of the presence of paraneoplastic antibodies.

Comparison of FDG and FDG-labeled leukocytes PET/CT in diagnosis of infection.

UNLABELLED: The aim of this study is to compare FDG and FDG-labeled leukocyte (WBC) PET/CT in the diagnosis of infection using different SUV and visual thresholds for interpretation. Patients, material, method: 49 consecutive patients (27 men, 22 women, mean age: 55.7 years, range: 16-89 years) with suspected musculoskeletal infection (n = 34), vascular graft infection (n = 5), aortitis (n =1 ), endocarditis (n = 1), mass lesion which is suspicious for infection or malignity (n = 6), and fever of unknown origin (n = 2) underwent both FDG and WBC-PET/CT. Images were evaluated by both visual analysis (grade 1-3) according to uptake intensity and quantitative grading (grade 1-3) based on lesion to background SUVmax values. Final diagnosis was made by histopathological, microbiological analysis or clinical-radiological work-up. RESULTS: The diagnosis of infection was made in total 24 patients, of whom 14 were diagnosed by histopathological and the rest by clinical-radiological work-up. WBC-PET/CT imaging with the visual threshold of 1b as infection positivity (for truncal lesions uptake equivalent to liver or lumbar vertebrae uptake; for extremity lesions uptake significantly higher than neighbouring soft tissue uptake or higher than neighbouring bone marrow uptake) was found to have the highest diagnostic accuracy (AUC: 0.874, CI: 0.771-0.997, p < 0.001). The optimal SUV threshold was found to be 8.8 (p = 0.006; sensitivity: 72.7%, specificity: 82.8) and 5.3 (p < 0.001; sensitivity: 81.8%, specificity: 79.3%) for FDG and WBC-PET/CT, respectively by ROC curve analysis. CONCLUSION: WBC-PET/CT is more valuable than FDG PET/CT in the imaging of infection. Visual threshold of >1b seems to be more suitable for detection of infection.

Pretherapy and posttherapy 18F-FDG PET/CT in isolated nasoseptal diffuse large B-cell lymphoma / 18F-FDG PET/TC pre y posterapia del Linfoma Difuso de Células B Grandes aislado en la zona nasoseptal

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Phase tracking and restoration of circadian rhythms by model-based optimal control.

Periodic cellular processes and especially circadian rhythms governed by the oscillating expression of a set of genes based on feedback regulation by their products have become an important issue in biology and medicine. The central circadian clock is an autonomous biochemical oscillator with a period close to 24 h. Research in chronobiology demonstrated that light stimuli can be used to delay or advance the phase of the oscillator, allowing it to influence the underlying physiological processes. Phase shifting and restoration of altered rhythms can generally be viewed as open-loop control problems that may be used for therapeutic purposes in diseases. A circadian oscillator model of the central clock mechanism is studied for the fruit fly Drosophila and show how model-based mixed-integer optimal control allows for the design of chronomodulated pulse-stimuli schemes achieving circadian rhythm restoration in mutants and optimal phase synchronisation between the clock and its environment.

Detection of metastases in patients with cutaneous melanoma using FDG-PET/CT.

This study aimed to detect metastases in patients with stage III or IV cutaneous melanoma by (18)F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT). Thirty-nine patients with clinically evident stage III or IV melanoma underwent whole-body FDG-PET/CT scans for metastatic disease and these results were compared with those of biopsy. Scans for 38 of the patients were evaluated; one patient's scan could not be evaluated. There were 11 true-positive, two false-positive, 24 true-negative and one false-negative scans for the detection of melanoma metastases, with sensitivity 91%, specificity 92%, accuracy 92%, and positive and negative predictive values 84% and 96%, respectively. False-positive FDG-PET/CT scans were due to sarcoidosis in the lung and infected cyst in the liver. It is concluded that FDG-PET/CT scanning has high sensitivity and specificity for detecting stage III or IV metastatic melanoma.

Standardized uptake values of normal organs on 18F-fluorodeoxyglucose positron emission tomography and computed tomography imaging.

Standardized uptake values (SUVs) of normal organs were evaluated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography and computed tomography (PET-CT) scanning. Seventy patients (38 men and 32 women) with no non-physiological 18F-FDG uptake participated in the study. All patients fasted for at least 4 h before PET-CT imaging and their fasting blood glucose levels were within the normal range. Image acquisition was performed after intravenous administration of 18F-FDG and images were obtained from the vertex to the upper thigh region. The SUVs of various organs were determined from the transverse views. The uptake of 18F-FDG was highest in the cerebrum, cerebellum, myocardium, tonsils, liver and spleen in both sexes. Having knowledge of the physiological uptake of 18F-FDG and normal organ SUVs is required for the correct interpretation of whole-body 18F-FDG-PET-CT studies.

Real-time nonlinear feedback control of pattern formation in (bio)chemical reaction-diffusion processes: a model study.

Theoretical and experimental studies related to manipulation of pattern formation in self-organizing reaction-diffusion processes by appropriate control stimuli become increasingly important both in chemical engineering and cellular biochemistry. In a model study, we demonstrate here exemplarily the application of an efficient nonlinear model predictive control (NMPC) algorithm to real-time optimal feedback control of pattern formation in a bacterial chemotaxis system modeled by nonlinear partial differential equations. The corresponding drift-diffusion model type is representative for many (bio)chemical systems involving nonlinear reaction dynamics and nonlinear diffusion. We show how the computed optimal feedback control strategy exploits the system inherent physical property of wave propagation to achieve desired control aims. We discuss various applications of our approach to optimal control of spatiotemporal dynamics.

Annihilation of limit-cycle oscillations by identification of critical perturbing stimuli via mixed-integer optimal control.

We present a novel model-based mixed-integer optimal control method to automatically identify the strength and timing of critical external stimuli leading to the transient annihilation of limit-cycle oscillators. Biochemical oscillators of this type play a central role in regulating cellular rhythms. Their specific manipulation is a promising perspective to control biological functions by drugs and tailored treatment strategies. We demonstrate our new optimal control approach in an application to a biochemical model for oscillatory calcium signal transduction.

Methemoglobinemia associated with acidosis of probable renal origin.

We describe an infant who had methemoglobinemia related to acidosis, probably on the basis of renal tubular acidosis. Methemoglobinemia may indicate the presence of a clinically significant underlying disorder.