Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

Estimating thyroid dose in pediatric CT exams from surface dose measurement.

The purpose of this study was to investigate the possibility of estimating pediatric thyroid doses from CT using surface neck doses. Optically stimulated luminescence dosimeters were used to measure the neck surface dose of 25 children ranging in ages between one and three years old. The neck circumference for each child was measured. The relationship between obtained surface doses and thyroid dose was studied using acrylic phantoms of various sizes and with holes of different depths. The ratios of hole-to-surface doses were used to convert patients' surface dose to thyroid dose. ImPACT software was utilized to calculate thyroid dose after applying the appropriate age correction factors. A paired t-test was performed to compare thyroid doses from our approach and ImPACT. The ratio of thyroid to surface dose was found to be 1.1. Thyroid doses ranged from 20 to 80 mGy. Comparison showed no statistical significance (p = 0.18). In addition, the average of surface dose variation along the z-axis in helical scans was studied and found to range between 5% (in 10 cm diameter phantom/24 mm collimation/pitch 1.0) and 8% (in 16 cm diameter phantom/12 mm collimation/pitch 0.7). We conclude that surface dose is an acceptable predictor for pediatric thyroid dose from CT. The uncertainty due to surface dose variability may be reduced if narrower collimation is used with a pitch factor close to 1.0. Also, the results did not show any effect of thyroid depth on the measured dose.

[Fortuitous discovery of intracerebral foreign body leads to the diagnosis of Munchausen syndrome by proxy]. / Un corps étranger intracérébral de découverte fortuite conduit au diagnostic du syndrome de Munchausen par procuration.

An intracerebral foreign body is a rare situation in childhood. It often occurs accidentally with transorbital or more rarely transnasal penetration. We report the case of a child who had been followed since the age of 2.5 months for chronic vomiting without failure to thrive. The fortuitous discovery at 22 months of age of a 4.5-cm-long sewing needle in his brain probably introduced via the fontanel led us to the diagnosis of Munchausen syndrome by proxy.

Characteristics of an OSLD in the diagnostic energy range.

PURPOSE: Optically stimulated luminescence (OSL) dosimetry has been recently introduced in radiation therapy as a potential alternative to the thermoluminescent dosimeter (TLD) system. The aim of this study was to investigate the feasibility of using OSL point dosimeters in the energy range used in diagnostic imaging. METHODS: NanoDot OSL dosimeters (OSLDs) were used in this study, which started with testing the homogeneity of a new packet of nanoDots. Reproducibility and the effect of optical treatment (bleaching) were then examined, followed by an investigation of the effect of accumulated dose on the OSLD indicated doses. OSLD linearity, angular dependence, and energy dependence were also studied. Furthermore, comparison with LiF:Mg,Ti TLD chips using standard CT dose phantoms at 80 and 120 kVp settings was performed. RESULTS: Batch homogeneity showed a coefficient of variation of <5%. Single-irradiation measurements with bleaching after each OSL readout was found to be associated with a 3.3% reproducibility (one standard deviation measured with a 8 mGy test dose), and no systematic change in OSLDs sensitivity could be noted from measurement to measurement. In contrast, the multiple-irradiation readout without bleaching in between measurements was found to be associated with an uncertainty (using a 6 mGy test dose) that systematically increased with accumulated dose, reaching 42% at 82 mGy. Good linearity was shown by nanoDots under general x-ray, CT, and mammography units with an R2 > 0.99. The angular dependence test showed a drop of approximately 70% in the OSLD response at 90 degrees in mammography (25 kVp). With the general radiography unit, the maximum drop was 40% at 80 kVp and 20% at 120 kVp, and it was only 10% with CT at both 80 and 120 kVp. The energy dependence study showed a range of ion chamber-to-OSLDs ratios between 0.81 and 1.56, at the energies investigated (29-62 keV). A paired t-test for comparing the OSLDs and TLDs showed no significant variation (p > 0.1). CONCLUSIONS: OSLDs exhibited good batch homogeneity (<5%) and reproducibility (3.3%), as well as a linear response. In addition, they showed no statistically significant difference with TLDs in CT measurements (p > 0.1). However, high uncertainty (42%) in the dose estimate was found as a result of relatively high accumulated dose. Furthermore, nanoDots showed high angular dependence (up to 70%) in low kVp techniques. Energy dependence of about 60% was found, and correction factors were suggested for the range of energies investigated. Therefore, if angular and energy dependences are taken into consideration and the uncertainty associated with accumulated dose is avoided, OSLDs (nanoDots) can be suitable for use as point dosimeters in diagnostic settings.

Influence of drug concentration on the diffusion parameters of caffeine.

BACKGROUND AND OBJECTIVES: In the fields of the pharmaceutical and cosmetic industries and in toxicology, the study of the skin penetration of molecules is very interesting. Various studies have considered the impact of different physicochemical drug characteristics, skin thickness, and formulations, on the transition from the surface of the skin to the underlying tissues or to the systemic circulation; however, the influence of drug concentration on the permeation flux of molecules has rarely been raised. Our study aims to discover the influence of caffeine concentration in a formulation on the percutaneous penetration from gels, as a result of different dose applications to polysulfate membrane and human skin. MATERIALS AND METHODS: For this purpose, three identical base gels were used at 1, 3, and 5% of caffeine, to evaluate the effect of the concentration of caffeine on in vitro release through the synthetic membrane and ex vivo permeation through the human skin, using diffusion Franz(TM) cells. RESULTS: The diffusion through the epidermal tissue was significantly slower than through the synthetic membrane, which recorded an increase of flux with an increase in the concentration of caffeine. The skin permeation study showed that diffusion depended not only on the concentration, but also on the deposited amount of gel. Nevertheless, for the same amount of caffeine applied, the flux was more significant from the less concentrated gel. CONCLUSION: Among all the different concentrations of caffeine examined, 1% gel of caffeine applied at 5 mg / cm(2) showed the highest absorption characteristics across human skin.

Determining uterine blood flow in pregnancy with magnetic resonance imaging.

OBJECTIVE: The purpose of this study is to determine the feasibility of measuring total uterine blood flow in pregnancy using magnetic resonance imaging (MRI) technique. METHODS: Uterine blood flow was determined in pregnant women in whom MRI was being carried out to assess a fetal anomaly. A two-dimensional time-of-flight magnetic resonance (MR) angiogram sequence was performed. Scout images and a peripherally gated phase contrast MR sequence were planned to study simultaneous blood flow in the uterine and ovarian arteries. RESULTS: The MR pelvic angiogram sequence was completed in 13 women. The uterine arteries were visualized and their cross-sectional area determined. The complexity of the pelvic blood supply prevented the calculation of blood flow velocity and, thus, total uterine blood flow. CONCLUSION: The measurement of total uterine blood flow during pregnancy was not possible using our MR technique. The ovarian vessels were not consistently visualized. Doppler ultrasonography remains the best modality by which to estimate total uterine blood flow in pregnancy.

Comparison of fetal biometric values with sonographic and 3D reconstruction MRI in term gestations.

OBJECTIVE: We sought to compare the fetal biometric values head and abdominal circumferences, biparietal and occipital-frontal diameters, and left and right ventricular atrial diameters obtained with contemporaneous sonography and 3D MRI reconstructions in term pregnancies. SUBJECTS AND METHODS: A total of 107 nulliparous women evaluated as having uncomplicated pregnancies and scheduled for induction at 42 completed weeks gave their informed consent and underwent MRI and sonography within 3 hours of each other. Two single-shot fast spin-echo MRI sequences were performed with 7- and 4-mm slice thicknesses and no gap. A single observer performed MRI postprocessing to obtain biometric values. A single sonographer using a 3- to 5-MHz curvilinear transducer performed transabdominal sonography. Concordance correlation and Bland-Altman analysis of differences were performed. RESULTS: Concordance correlation was poor for both right (0.024) and left (0.005) ventricular atrial diameters. There were moderate concordance correlations for head (0.56) and abdominal (0.53) circumferences and biparietal diameter (0.61). Occipital-frontal diameter had fair correlation (0.27). CONCLUSION: Comparison between contemporaneous sonographic and 3D reconstructed MR images at late gestational ages shows acceptable correlation between the two techniques for head circumference, abdominal circumference, and biparietal diameter.

MR volume of the fetal cerebellum in relation to growth.

PURPOSE: To quantify fetal cerebellar growth by measuring cerebellar volumes of normal fetuses throughout gestation with MRI. MATERIALS AND METHODS: A total of 93 fetuses with normal brains ranging in age from 16 to 40 gestational weeks were included in the study. Standard fetal biometric measurements were made on a three-dimensional postprocessing workstation and included the head circumference, transverse cerebellar diameter, biparietal diameter, occipital-frontal diameter, as well as cerebellar volume. The gestational ages were estimated from fetal head circumference measurements. Regression analysis was used to find the best-fit model. RESULTS: There is a strong correlation describing cerebellar volume and gestational age in fetuses with normal central nervous systems. A second-order polynomial regression model was found to be the most appropriate descriptor of cerebellar volume in relation to normal fetal growth. In addition, the cerebellar volume was also found to correlate strongly with the common fetal biometric measurements of transverse cerebellar diameter, biparietal diameter, and occipital-frontal diameter. CONCLUSION: Nomograms for fetal cerebellar volume with gestational age derived from head circumference measurements are presented for the first time with MRI. A normal fetal cerebellar volume growth chart is established. These results should prove helpful in defining situations of abnormal growth development and dysmorphology.

Magnetic resonance imaging pelvimetry and the prediction of labor dystocia.

OBJECTIVE: To study whether magnetic resonance imaging (MRI) pelvimetry has the ability to identify those women who require cesarean delivery for labor dystocia. METHODS: From July 2003 to April 2004, nulliparous women scheduled for a labor induction for prolonged pregnancy (42 weeks) were asked to participate in a pelvimetry study. Those who consented underwent fast-acquisition MRI that included two 90-second acquisitions to evaluate fetal biometry and volumetry and maternal pelvimetry, including novel measurements of pelvic bony and soft tissue volumes as determined by MRI. Information about each patient's pregnancy, labor course, and neonatal outcome was prospectively collected. Pelvimetry results for those women undergoing operative delivery for labor dystocia were compared with those who did not. Single fetal and maternal pelvic measurements, as well as ratios of both, were analyzed. In addition, previously described radiographic pelvimetry techniques and formulas to predict dystocia were used. RESULTS: One hundred one women underwent MRI, and 22 of these underwent cesarean delivery for dystocia. No single fetal measurement was statistically associated with dystocia. Several maternal pelvic measures, fetal-to-maternal ratios, and previously reported pelvimetric techniques were significantly associated with dystocia. The ratio of magnetic resonance (MR) fetal head volume to pelvic soft tissue volume had statistical significance (P = .04). Receiver operator characteristic curves were developed for the different measurements, ratios, and formulas studied to assess whether any of the techniques could accurately predict labor dystocia requiring operative delivery. The area under the curve values ranged from 0.6 to 0.8, with the ratio of MR head volume to pelvic soft tissue being 0.7. These values suggest that MRI can identify those women at greatest risk for dystocia, but it cannot with accuracy predict which ones will require a cesarean. CONCLUSION: We found significant associations with MRI pelvimetry and labor dystocia, but MRI was not a significant improvement over previously described pelvimetric techniques. LEVEL OF EVIDENCE: II-3.

The effect of magnesium sulfate on large cerebral artery blood flow in preeclampsia.

OBJECTIVES: To determine the effect of a 6 gram intravenous bolus of magnesium sulfate on maternal cerebral blood flow in women with preeclampsia. STUDY DESIGN: Velocity-encoded phase-contrast magnetic resonance imaging studies were performed on twelve preeclamptic women prior to and immediately after infusion of a 6 gram magnesium sulfate loading dose. Cerebral blood flow was determined at the bilateral proximal middle and posterior cerebral arteries. Study participants returned 6 weeks postpartum for a non-pregnant measurement of cerebral blood flow. The Wilcoxon paired-sample test was used with statistical significance defined as p<0.05. RESULTS: There was no significant difference in cerebral vessel diameter nor blood flow for any of the examined arteries between the pre- and post magnesium sulfate therapy states. CONCLUSIONS: The absence of a significant difference in cerebral blood flow of the middle and posterior cerebral arteries before and after infusion of a 6 gram loading dose of magnesium sulfate in women with preeclampsia could suggest the absence of vasoconstriction of the large cerebral arteries in preeclampsia and question the role of magnesium sulfate as a vasodilator of these arteries.

Increased cerebral blood flow in preeclampsia with magnetic resonance imaging.

OBJECTIVE: The purpose of this study was to compare third trimester and nonpregnant cerebral blood flow of women with preeclampsia to normotensive control subjects with the use of magnetic resonance imaging techniques. STUDY DESIGN: Nine normotensive pregnant women and 12 untreated women with preeclampsia underwent velocity-encoded phase contrast magnetic resonance imaging of the bilateral middle and posterior cerebral arteries in the third trimester and at 6 to 8 weeks after delivery. The Student t test was used for comparison, with a probability value of <.05 considered significant. RESULTS: Third-trimester large cerebral artery blood flow was significantly higher in preeclampsia. Mean vessel diameter was unchanged, except for the left posterior cerebral artery. There was no difference in mean vessel diameter or cerebral blood flow between the 2 groups while the women were not pregnant. CONCLUSION: Cerebral blood flow is increased significantly in preeclampsia. We hypothesize that increased cerebral blood flow ultimately could lead to eclampsia through hyperperfusion and the development of vasogenic edema.

[Thromboses of heart valve prostheses: predisposing and prognostic factors based on a study of 41 patients]. / Thromboses de prothèses valvulaires cardiaques: facteurs favorisants et pronostiques à partir d'une étude portant sur 41 patients.

Forty one patients were admitted with a diagnosis of prosthetic valve thrombosis. One patient was thrombolyzed successfully, and 40 underwent surgical procedures. In 13 cases, prosthetic valve thrombosis occurred in the first month after valve replacement. 18 patients were in functional class IV of the NYHA classification. Among the thrombosed prostheses, 91% were mechanical, and 61% in mitral position. Adequacy of anticoagulation was the most important risk factor, as this treatment was inappropriate in 20 patients. In 10 other patients, it had been changed for medical (bleeding events, pregnancy) or surgical (non cardiac surgery) reasons. The perioperative mortality rate was high (32.4%). It was 12% in patients in functional class II and 46% in those in class IV (p < 0.05). This underlines the value of early diagnosis, in which echocardiography, especially with a transesophageal probe, takes a major place, allowing prompt surgical treatment.

[Thrombosis of heart valve prostheses: favourable and prognostic factors based on a study of 41 patients]. / Thromboses de prothèses valvulaires cardiaques: facteurs favorisants et pronostiques à partir d'une étude portant sur 41 patients.

Forty one patients were admitted with a diagnosis of prosthetic valve thrombosis. One patient was thrombolysed successfully, and 40 underwent surgical procedures. In 13 cases, prosthetic valve thrombosis occurred in the first month after valve replacement. 18 patients were in functional class IV of the NYHA classification. Among the thrombosed prostheses, 91% were mechanical, and 61% in mitral position. Adequacy of anti-coagulation was the most important risk factor, as this treatment was inappropriate in 20 patients. In 10 other patients, it had been changed for medical (bleeding events, pregnancy) or surgical (non cardiac surgery) reasons. The perioperative mortality rate was high (32.4%). It was 12% in patients in functional class II and 46% in those in class IV (p < 0.05). This underlines the value of early diagnosis, in which echocardiography, especially with a transesophageal probe, takes a major place, allowing prompt surgical treatment.

[C-reactive protein in bacterial meningitis in adults]. / La protéine c-réactive dans les méningites bactériennes de l'adulte.

In order to assess the benefits of serial assays of C-reactive protein in the course of bacterial meningitis in adults, daily blood samples were taken for CRP measurement during 10 days in 21 consecutive patients (mean age: 24 +/- 8 years) hospitalized for bacterial meningitis principally due to Neisseria meningitidis (n = 15). The highest CRP level (178 +/- 38 mg/l) was present on admission, followed by a regular decrease occurring in uncomplicated meningitis until normal level was achieved on day 9. The CRP kinetics was not influenced by the type of causative micro-organism. This study shows that CRP kinetics in adults is similar to that reported in children. The benefit of CRP assays in optimizing the duration of antibiotic treatment of meningitis needs to be more carefully assessed.

[Chylothorax caused by thrombosis of the superior vena cava in Behçet's disease]. / Chylothorax par thrombose de la veine cave supérieure au cours d'une maladie de Behçet.

The occurrence of chylothorax due to thrombosis of the subclavicular venous drainage is reported. This occurred in a young adult with previously undiagnosed Behçet's disease which had been developing over three years. Venous thromboses during the course of Behçet's disease are extremely frequent and are currently one of the diagnostic criteria. When these thromboses involve the central veins, in particularly the superior vena cava or one of its branches a chylothorax is possible due to blockage of the lymphatic circulation and may be a grave complication, given its location.