Modeling spheroid growth, PET tracer uptake, and treatment effects of the Hsp90 inhibitor NVP-AUY922.

For a PET agent to be successful as a biomarker in early clinical trials of new anticancer agents, some conditions need to be fulfilled: the selected tracer should show a response that is related to the antitumoral effects, the quantitative value of this response should be interpretable to the antitumoral action, and the timing of the PET scan should be optimized to action of the drug. These conditions are not necessarily known at the start of a drug-development program and need to be explored. We proposed a translational imaging activity in which experiments in spheroids and later in xenografts are coupled to modeling of growth inhibition and to the related changes in the kinetics of PET tracers and other biomarkers. In addition, we demonstrated how this information can be used for planning clinical trials. METHODS: The first part of this concept is illustrated in a spheroid model with BT474 breast cancer cells treated with the heat shock protein 90 (Hsp90) inhibitor NVP-AUY922. The growth-inhibitory effect after a pulse treatment with the drug was measured with digital image analysis to determine effects on volume with high accuracy. The growth-inhibitory effect was described mathematically by a combined E(max) and time course model fitted to the data. The model was then used to simulate a once-per-week treatment; in these experiments the uptake of the PET tracers (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was determined at different doses and different time points. RESULTS: A drug exposure of 2 h followed by washout of the drug from the culture medium generated growth inhibition that was maximal at the earliest time point of 1 d and decreased exponentially with time during 10-12 d. The uptake of (18)F-FDG per viable tumor volume was minimally affected by the treatment, whereas the (18)F-FLT uptake decreased in correlation with the growth inhibition. CONCLUSION: The study suggests a prolonged action of the Hsp90 inhibitor that supports a once-per-week schedule. (18)F-FLT is a suitable tracer for the monitoring of effect, and the (18)F-FLT PET study might be performed within 3 d after dosing.     

Evaluation of an accelerated protocol for detection of extended-spectrum beta-lactamase-producing gram-negative bacilli from positive blood cultures

We evaluated a protocol for the accelerated detection of extended-spectrum beta-lactamases (ESBLs) in gram-negative bloodstream pathogens. Two hundred eighty-three blood culture bottles were subjected to direct ESBL testing by inoculating samples directly from blood culture bottles onto agar plates containing cefotaxime and ceftazidime disks, with and without clavulanate. Standard ESBL testing in accordance with the NCCLS guidelines after subculturing on agar plates was performed in parallel. Results of the direct ESBL testing were reported 2.3 days sooner and were comparable to those of the standard NCCLS method with sensitivity, specificity, and positive and negative predictive values of 100, 98, 94, and 100%, respectively.     

Natural language processing and entrustable professional activity text feedback in surgery: A machine learning model of resident autonomy

BackgroundEntrustable Professional Activities (EPAs) contain narrative ‘entrustment roadmaps’ designed to describe specific behaviors associated with different entrustment levels. However, these roadmaps were created using expert committee consensus, with little data available for guidance. Analysis of actual EPA assessment narrative comments using natural language processing may enhance our understanding of resident entrustment in actual practice.MethodsAll text comments associated with EPA microassessments at a single institution were combined. EPA—entrustment level pairs (e.g. Gallbladder Disease—Level 1) were identified as documents. Latent Dirichlet Allocation (LDA), a common machine learning algorithm, was used to identify latent topics in the documents associated with a single EPA. These topics were then reviewed for interpretability by human raters.ResultsOver 18 months, 1015 faculty EPA microassessments were collected from 64 faculty for 80 residents. LDA analysis identified topics that mapped 1:1 to EPA entrustment levels (Gammas >0.99). These LDA topics appeared to trend coherently with entrustment levels (words demonstrating high entrustment were consistently found in high entrustment topics, word demonstrating low entrustment were found in low entrustment topics).ConclusionsLDA is capable of identifying topics relevant to progressive surgical entrustment and autonomy in EPA comments. These topics provide insight into key behaviors that drive different level of resident autonomy and may allow for data-driven revision of EPA entrustment maps.     

Multifocal Parotid Oncocytic Cystadenomatosis: A Rare Process that Can Mimic Malignancy

Multifocal cystic oncocytosis (MCO) is a rare, benign process accounting for approximately 0.1% of salivary gland lesions. Salivary oncocytosis is characterized by multiple unencapsulated solid nodules of oncocytic cells derived from transformed striated ducts. MCO is a variant of salivary oncocytosis which manifests as cystically dilated striated ducts. It is difficult to obtain a definitive preoperative diagnosis of MCO; therefore, these lesions are commonly treated with surgery. We report the unique case of a 66-year-old male who previously underwent a superficial left parotidectomy for a pleomorphic adenoma. Four years later, he presented with clinical and radiographic suspicion of a multifocal recurrent pleomorphic adenoma. The patient subsequently underwent a revision parotidectomy. However, final pathology confirmed a diagnosis of MCO. Although MCO is commonly treated with surgery due to lack of a definitive preoperative diagnosis, surgery is unnecessary outside of diagnostic, functional or cosmetic considerations. Thus, if a patient with parotid oncocytosis treated by superficial parotidectomy develops disease re-manifestation in the residual deep lobe, further surgery is not indicated. There is no risk of malignant progression in this process. We report on this unusual entity as it may mimic salivary malignancy or, as in this case, recurrence of benign disease.     

Motor Developmental Status of Moderately Low Birth Weight Preterm Infants

Objective: Motor development is frequently reported to be impaired in very low birth weight (VLBW) infants, but little is known about the moderately low birth weight (MLBW) infants. The aim of this study was to investigate whether MLBW preterm infants present developmental delay. Methods: In a historical cohort study, 18±2 month-old infants with a history of low birth weight (LBW) were identified. All infants with complications of LBW with negative effects on development were excluded. Healthy infants with normal birth weight (2500–4000 g) were included as controls. All infants were evaluated by the Peabody Developmental Motor Scale II (PDMS-2) test and final scores compared between the two groups. Finding: 88 infants including 58 MLBW and 30 NBW with a mean birth weight of 1900±382.4 g and 3150±473.5 g respectively, were studied. In the MLBW group, gross and fine motor skill scores were below average in 6 (6.8%) and 10 (17%) infants, respectively. There were no significant differences between the two groups according to gross motor quotient (102.5±5.5 in NBW vs 100.1±7.2 in MLBW; P=0.1), but MLBW infants achieved significantly lower scores in fine motor (93.3±5.4 vs 99.6±5.0; P=0.001) and total motor quotient (97.0±5.9 vs 101.53±5.0; P=0.001). Conclusion: The finding of this study show developmental defects in fine motor skills in MLBW infants. Accurate monitoring of the developmental status of this population should be emphasized for an earlier recognition and intervention.Key Words: Low Birth Weight, Peabody Developmental Motor Scale II (PDMS-2), Motor Development, Infant     

Gadolinium for hysterosalpingography

OBJECTIVE: To evaluate the use of gadolinium as an alternative to iodinated contrast medium for hysterosalpingography in patients with an increased risk for iodinated contrast hypersensitivity. STUDY DESIGN: Between March 2003 and March 2006, 3,616 hysterosalpingography examinations were performed. Hysterosalpingography was routinely performed using water-soluble, nonionic, iodinated contrast medium. Hysterosalpingography was performed with gadolinium in patients at risk for contrast hypersensitivity. We retrospectively reviewed the diagnostic quality, safety and clinical outcome in patients who underwent gadolinium hysterosalpingography. RESULTS: Hysterosalpingograms of diagnostic quality were successfully performed without adverse reactions in 11 patients. The density of gadolinium contrast opacification was diminished as compared with a conventional hysterosalpingogram with iodinated contrast. Two of the 8 patients who were not on oral contraceptives and had patent fallopian tubes became pregnant within 6 months of the hysterosalpingogram procedure. CONCLUSION: Gadolinium hysterosalpingography is of diagnostic value and is a safe alternative to iodinated contrast medium for hysterosalpingography in patients at increased risk for iodinated contrast hypersensitivity.     

An Iranian herbal-marine medicine, MS14, ameliorates experimental allergic encephalomyelitis

Multiple sclerosis is an inflammatory and demyelinating disease of the central nervous system which mainly affects young adults. To overcome wide spectrum troublesome symptoms of multiple sclerosis which affects the quality of life both in patients and their families, new drugs and remedies have been examined and offered. The preclinical beneficial effects of different medicines have mostly been examined in an animal model of multiple sclerosis called experimental allergic encephalomyelitis (EAE). In this study we have tested a traditionally used natural (herbal-marine) product called MS(14) in EAE mice. EAE mice were fed with MS(14) containing diet (30%) on the immunization day and monitored for 20 days. The results show that while clinical scores and therefore severity of the disease was progressive in normal-fed EAE mice, the disease was slowed down in MS(14)-fed EAE mice. Moreover, while there were moderate to severe neuropathological changes in normal fed mice, milder changes were seen in MS(14) fed mice.