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Cortisol diurnal variation may be abnormal among patients with endogenous Cushing syndrome (CS). The study objective was to compare the plasma cortisol AM/PM ratios between different etiologies of CS. This is a retrospective cohort study, conducted at a clinical research center. Adult patients with CS that underwent adrenalectomy or trans-sphenoidal surgery (n=105) were divided to those with a pathologically confirmed diagnosis of Cushing disease (n=21) and those with primary adrenal CS, including unilateral adrenal adenoma (n=28), adrenocortical hyperplasia (n=45), and primary pigmented nodular adrenocortical disease (PPNAD, n=11). Diurnal plasma cortisol measurements were obtained at 11:30 PM and midnight and at 7:30 and 8:00 AM. The ratios between the mean morning levels and mean late-night levels were calculated. Mean plasma cortisol AM/PM ratio was lower among CD patients compared to those with primary adrenal CS (1.4±0.6 vs. 2.3±1.5, p15 pg/ml) excludes CD with a 85.0% specificity and a negative predictive value (NPV) of 90.9%. Among patients with primary adrenal CS, an AM/PM cortisol≥1.2 had specificity and NPV of 100% for ruling out a diagnosis of PPNAD. Plasma cortisol AM/PM ratios are lower among patients with CD compared with primary adrenal CS, and may aid in the differential diagnosis of endogenous hypercortisolemia.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare type of bilateral adrenal hyperplasia leading to hypercortisolemia. Adrenal nodularity is often appreciable with computed tomography (CT); however, accurate radiologic characterization of adrenal size in PPNAD has not been studied well. We used 3-dimensional (3D) volumetric analysis to characterize and compare adrenal size in PPNAD patients, with and without Cushing's syndrome (CS). Patients diagnosed with PPNAD and their family members with known mutations in PRKAR1A were screened. CT scans were used to create 3D models of each adrenal. Criteria for biochemical diagnosis of CS included loss of diurnal variation and/or elevated midnight cortisol levels, and paradoxical increase in urinary free cortisol and/or urinary 17-hydroxysteroids after dexamethasone administration. Forty-five patients with PPNAD (24 females, 27.8±17.6 years) and 8 controls (19±3 years) were evaluated. 3D volumetric modeling of adrenal glands was performed in all. Thirty-eight patients out of 45 (84.4%) had CS. Their mean adrenal volume was 8.1 cc±4.1, 7.2 cc±4.5 (p=0.643) for non-CS, and 8.0cc±1.6 for controls. Mean values were corrected for body surface area; 4.7 cc/kg/m(2)±2.2 for CS, and 3.9 cc/kg/m(2)±1.3 for non-CS (p=0.189). Adrenal volume and midnight cortisol in both groups was positively correlated, r=0.35, p=0.03. We conclude that adrenal volume measured by 3D CT in patients with PPNAD and CS was similar to those without CS, confirming empirical CT imaging-based observations. However, the association between adrenal volume and midnight cortisol levels may be used as a marker of who among patients with PPNAD may develop CS, something that routine CT cannot do.

Computer-aided diagnosis systems aim to assist clinicians in the early identification of abnormal signs in order to optimize the interpretation of medical images and increase diagnostic precision. Multiple sclerosis (MS) and clinically isolated syndrome (CIS) are chronic inflammatory, demyelinating diseases affecting the central nervous system. Recent advances in deep learning (DL) techniques have led to novel computational paradigms in MS and CIS imaging designed for automatic segmentation and detection of areas of interest and automatic classification of anatomic structures, as well as optimization of neuroimaging protocols. To this end, there are several publications presenting artificial intelligence-based predictive models aiming to increase diagnostic accuracy and to facilitate optimal clinical management in patients diagnosed with MS and/or CIS. The current study presents a thorough review covering DL techniques that have been applied in MS and CIS during recent years, shedding light on their current advances and limitations., Competing Interests: DAS is the Editor-in-Chief of the journal, but had no personal involvement in the reviewing process, or any influence in terms of adjudicating on the final decision for this article. All the authors declare that they have no competing interests., (Copyright: © Kontopodis et al.)

Purpose: We examined abnormal pituitary imaging (API) and associated endocrine dysfunction in subjects with ECD., Methods: A cross-sectional descriptive examination of a natural history cohort study diagnosed with ECD was conducted at a clinical research center. Subjects underwent baseline endocrine tests of anterior and posterior pituitary function and dedicated pituitary gland MRI scans. We determined the frequency of various pituitary imaging abnormalities in ECD and assessed its relationships with age, sex, body mass index (BMI), BRAF V600E status, high sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), pituitary hormone deficits and number, diabetes insipidus (DI), and panhypopituitarism., Results: Our cohort included 61 subjects with ECD [age (SD): 54.3 (10.9) y, 46 males/15 females]. API was present in 47.5% (29/61) of ECD subjects. Loss of the posterior pituitary bright spot (36.1%) followed by thickened pituitary stalk (24.6%), abnormal enhancement (18.0%), and pituitary atrophy (14.8%) were the most common abnormalities. DI and panhypopituitarism were more frequent in subjects with API without differences in age, sex distribution, hsCRP, ESR, and BRAF V600E status compared to normal pituitary imaging., Conclusions: We noted a high burden of API and endocrinopathies in ECD. API was highly associated with the presence of panhypopituitarism and DI. Therefore, a thorough assessment of hypothalamic-pituitary integrity should be considered in subjects with ECD.

Melorheostosis is a rare disease of bone overgrowth that is primarily diagnosed based on imaging studies. Recently, the association of different radiological patterns of the disease with distinct genetic cause was reported. Several case reports have described the radiological findings in patients with melorheostosis. However, the added value of cross-sectional imaging with CT and MRI beyond X-rays has not been investigated. The aim of the current study was to investigate this existing gap in knowledge. Forty patients with melorheostosis seen at the National Institute of Health Clinical Center were included in the study, and all their imaging studies were analyzed. The sequence of interpretation was X-ray followed by CT and then MRI. CT images were extracted from whole-body 18F-sodium fluoride positron emission tomography/CT studies. The information from CT reclassified the initial X-rays based radiological pattern in 13 patients. Additionally, CT comprehensively identified joint involvement and disease extent. In 76% of patients ( n = 29) who underwent MRI, additional findings were noted, ranging from soft tissue edema to identification of soft tissue masses and incidental findings. MRI did not provide additional information on skeletal lesions beyond CT scans. However, it revealed the extension of soft tissue ossification into ischiofemoral space in four patients who complained of deep gluteal pain consistent with ischiofemoral impingement syndrome. In addition, MRI revealed soft tissue edema in 20 patients, 9 of whom had bone marrow edema and periosteal edema in the tibias consistent with shin splints. These findings suggest that select patients with melorheostosis should be evaluated with both CT and MRI, particularly patients in whom the distribution of pain does not correlate with the anatomic location of the disease in plain radiographs. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research., Competing Interests: The authors declare that there is no conflict of interests that could be perceived as prejudicing the impartiality of the research reported., (© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.)

The coronavirus pandemic and its unprecedented consequences globally has spurred the interest of the artificial intelligence research community. A plethora of published studies have investigated the role of imaging such as chest X-rays and computer tomography in coronavirus disease 2019 (COVID-19) automated diagnosis. Οpen repositories of medical imaging data can play a significant role by promoting cooperation among institutes in a world-wide scale. However, they may induce limitations related to variable data quality and intrinsic differences due to the wide variety of scanner vendors and imaging parameters. In this study, a state-of-the-art custom U-Net model is presented with a dice similarity coefficient performance of 99.6% along with a transfer learning VGG-19 based model for COVID-19 versus pneumonia differentiation exhibiting an area under curve of 96.1%. The above was significantly improved over the baseline model trained with no segmentation in selected tomographic slices of the same dataset. The presented study highlights the importance of a robust preprocessing protocol for image analysis within a heterogeneous imaging dataset and assesses the potential diagnostic value of the presented COVID-19 model by comparing its performance to the state of the art., (Copyright: © Trivizakis et al.)

Context: Radiological characterization of adrenal size in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) has not been previously investigated., Objective: We hypothesized that volumetric modeling of adrenal gland size may correlate with biochemical disease severity in patients with PBMAH. Secondary analysis of patients with concurrent primary aldosteronism (PA) was performed., Design: A retrospective cross-sectional analysis of 44 patients with PBMAH was conducted from 2000 to 2019., Setting: Tertiary care clinical research center., Patients: Patients were diagnosed with PBMAH based upon clinical, genetic, radiographic and biochemical characteristics., Intervention: Clinical, biochemical, and genetic data were obtained. Computed tomography scans were used to create volumetric models by manually contouring both adrenal glands in each slice using Vitrea Core Fx v6.3 software (Vital Images, Minnetonka, Minnesota)., Main Outcome and Measures: 17-hydroxycorticosteroids (17-OHS), ARMC5 genetics, and aldosterone-to-renin ratio (ARR) were retrospectively obtained. Pearson test was used for correlation analysis of biochemical data with adrenal volume., Results: A cohort of 44 patients with PBMAH was evaluated, with a mean age (±SD) of 53 ± 11.53. Eight patients met the diagnostic criteria for PA, of whom 6 (75%) were Black. In the Black cohort, total adrenal volumes positively correlated with midnight cortisol (R = 0.76, P  = 0.028), urinary free cortisol (R = 0.70, P  = 0.035), and 17-OHS (R = 0.87, P  = 0.0045), with a more pronounced correlation with left adrenal volume alone. 17-OHS concentration positively correlated with total, left, and right adrenal volume in patients harboring pathogenic variants in ARMC5 (R = 0.72, P  = 0.018; R = 0.65, P  = 0.042; and R = 0.73, P  = 0.016, respectively)., Conclusions: Volumetric modeling of adrenal gland size may associate with biochemical severity in patients with PBMAH, with particular utility in Black patients., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Importance: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis affecting multiple organs and commonly caused by somatic pathogenic variants in BRAF V600E and mitogen-activated protein kinase genes. Clinical features of ECD result from histiocytic involvement of various tissues; while endocrine involvement in ECD occurs frequently, the prevalence of central or primary hypothyroidism has not been thoroughly investigated., Objective: To assess hypothalamus-pituitary-thyroid (HPT) dysfunction in patients with ECD., Design, Setting, and Participants: This cross-sectional study included 61 patients with ECD who were enrolled in a natural history study at a tertiary care center between January 2011 and December 2018. ECD was diagnosed on the basis of clinical, genetic, and histopathological features. Data were analyzed in March 2020., Exposure: Diagnosis of ECD., Main Outcomes and Measures: Main outcome was the prevalence of thyroid dysfunction in adults with ECD compared with community estimates. Patients underwent baseline evaluation with a thyroid function test, including thyrotropin, free thyroxine (fT4), and total thyroxine (T4), and sellar imaging with magnetic resonance imaging or computed tomography scan. The association of HPT dysfunction was assessed for differences in age, sex, body mass index, BRAF V600E status, high sensitivity C-reactive protein level, sellar imaging, and pituitary hormonal dysfunction., Results: A total of 61 patients with ECD (46 [75%] men; mean [SD] age, 54.3 [10.9] years) were evaluated. Seventeen patients (28%) had hypothyroidism requiring levothyroxine therapy. The prevalence of both central and primary hypothyroidism were higher than community estimates (central hypothyroidism: 9.8% vs 0.1%; odds ratio, 109.0; 95% CI, 37.4-260.6; P < .001; primary hypothyroidism: 18.0% vs 4.7%; OR, 4.4; 95% CI, 2.1-8.7; P < .001). Patients with hypothyroidism (both primary and central), compared with patients with euthyroidism, had higher body mass index (median [interquartile range] 31.4 [28.3-38.3] vs 26.7 [24.4-31.9]; P = .004) and a higher prevalence of panhypopituitarism (7 [47%] vs 3 [7%]; P < .001). Among patients with hypothyroidism, those with central hypothyroidism, compared with patients with primary hypothyroidism, had a lower mean (SD) body mass index (28.3 [2.6] vs 36.3 [5.9]; P = .007) and higher frequencies of abnormal sellar imaging (5 [83%] vs 3 [27%]; P = .050) and panhypopituitarism (5 [83%] vs 3 [27%]; P = .050)., Conclusions and Relevance: In this cohort study, a higher prevalence of central and primary hypothyroidism was identified in patients with ECD compared with the community. There should be a low threshold for testing for hypothyroidism in patients with ECD, and treatment should follow standard guidelines.

Patients with chronic stroke have currently little hope for motor improvement towards regaining independent activities of daily living; stem cell treatments offer a new treatment option and needs to be developed. Patients with chronic stroke (more than 3 months prior to stem cell treatment, mean 21.2 months post-stroke) were treated with CD271 + stem cells, 7 patients received autologous and 1 allogeneic cells from first degree relative; administration was intravenous in 1 and intrathecal in 7 patients. Each patient received a single treatment consisting of 2-5x10 6 cells/kg and they were followed up for up to 12 months. There were significant improvements in expressive aphasia (2/3 patients) spasticity (5/5, of which 2 were transient), and small improvements in motor function (2/8 patients). Although motor improvements were minor in our chronic stroke patients, improvements in aphasia and spasticity were significant and in the context of good safety we are advocating further administration and clinical studies of CD271 + stem cells not only in chronic stroke patients, but also for spastic paresis/plegia; a different, yet unexplored application is pulmonary emphysema., Competing Interests: DAS is the Editor-in-Chief for the journal, but had no personal involvement in the reviewing process, or any influence in terms of adjudicating on the final decision, for this article. The other authors declare that they have no competing interests., (Copyright: © Stancioiu et al.)

Blood-brain barrier opening (BBBO) with pulsed Focused Ultrasound (pFUS) and microbubbles (MB) has received increasing interest as a method for neurotherapeutics of the central nervous system. In general, conventional MRI [i.e., T2w, T2 ∗ w, gadolinium (Gd) enhanced T1w] is used to monitor the effects of pFUS+MB on BBBO and/or assess whether sonication results in parenchymal damage. This study employed multimodal MRI techniques and 18 F-Fludeoxyglucose (FDG) PET to evaluate the effects of single and multiple weekly pFUS+MB sessions on morphology and glucose utilization levels in the rat cortex and hippocampus. pFUS was performed with 0.548 MHz transducer with a slow infusion over 1 min of Optison TM (5-8 × 10 7 MB) in nine focal points in cortex and four in hippocampus. During pFUS+MB treatment, Gd-T1w was performed at 3 T to confirm BBBO, along with subsequent T2w, T2 ∗ w, DTI and glucose CEST (glucoCEST)-weighted imaging by high field 9.4 T and compared with FDG-PET and immunohistochemistry. Animals receiving a single pFUS+MB exhibited minimal hypointense voxels on T2 ∗ w. Brains receiving multiple pFUS+MB treatments demonstrated persistent T2w and T2 ∗ abnormalities associated with changes in DTI and glucoCEST when compared to contralateral parenchyma. Decreased glucoCEST contrast was substantiated by FDG-PET in cortex following multiple sonications. Immunohistochemistry showed significantly dilated vessels and decreased neuronal glucose transporter (GLUT3) expression in sonicated cortex and hippocampus without changes in neuronal counts. These results suggest the importance to standardize MRI protocols in concert with advanced imaging techniques when evaluating long term effects of pFUS+MB BBBO in clinical trials for neurological diseases., (Copyright © 2020 Tu, Kovacs, Sundby, Witko, Papadakis, Reid, Hammoud and Frank.)

We are being confronted with the most consequential pandemic since the Spanish flu of 1918‑1920 to the extent that never before have 4 billion people quarantined simultaneously; to address this global challenge we bring to the forefront the options for medical treatment and summarize SARS‑CoV2 structure and functions, immune responses and known treatments. Based on literature and our own experience we propose new interventions, including the use of amiodarone, simvastatin, pioglitazone and curcumin. In mild infections (sore throat, cough) we advocate prompt local treatment for the naso‑pharynx (inhalations; aerosols; nebulizers); for moderate to severe infections we propose a tried‑and‑true treatment: the combination of arginine and ascorbate, administered orally or intravenously. The material is organized in three sections: i) Clinical aspects of COVID‑19; acute respiratory distress syndrome (ARDS); known treatments; ii) Structure and functions of SARS‑CoV2 and proposed antiviral drugs; iii) The combination of arginine‑ascorbate.

COVID-19 has led to an unprecedented healthcare crisis with millions of infected people across the globe often pushing infrastructures, healthcare workers and entire economies beyond their limits. The scarcity of testing kits, even in developed countries, has led to extensive research efforts towards alternative solutions with high sensitivity. Chest radiological imaging paired with artificial intelligence (AI) can offer significant advantages in diagnosis of novel coronavirus infected patients. To this end, transfer learning techniques are used for overcoming the limitations emanating from the lack of relevant big datasets, enabling specialized models to converge on limited data, as in the case of X-rays of COVID-19 patients. In this study, we present an interpretable AI framework assessed by expert radiologists on the basis on how well the attention maps focus on the diagnostically-relevant image regions. The proposed transfer learning methodology achieves an overall area under the curve of 1 for a binary classification problem across a 5-fold training/testing dataset., (Copyright: © Tsiknakis et al.)

This study aims to examine a time-extended dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) protocol and report a comparative study with three different pharmacokinetic (PK) models, for accurate determination of subtle blood-brain barrier (BBB) disruption in patients with multiple sclerosis (MS). This time-extended DCE-MRI perfusion protocol, called Snaps, was applied on 24 active demyelinating lesions of 12 MS patients. Statistical analysis was performed for both protocols through three different PK models. The Snaps protocol achieved triple the window time of perfusion observation by extending the magnetic resonance acquisition time by less than 2 min on average for all patients. In addition, the statistical analysis in terms of adj- R 2 goodness of fit demonstrated that the Snaps protocol outperformed the conventional DCE-MRI protocol by detecting 49% more pixels on average. The exclusive pixels identified from the Snaps protocol lie in the low k trans range, potentially reflecting areas with subtle BBB disruption. Finally, the extended Tofts model was found to have the highest fitting accuracy for both analyzed protocols. The previously proposed time-extended DCE protocol, called Snaps, provides additional temporal perfusion information at the expense of a minimal extension of the conventional DCE acquisition time., Competing Interests: Conflict of interest: The authors state no conflict of interest., (© 2020 Eleftherios Kontopodis et al., published by De Gruyter.)

Competing Interests: Conflict of Interest: None

Summary: Adrenococortical carcinoma (ACC) is a rare cancer, occurring at the rate of one case in two million person years. Cushing syndrome or a mixed picture of excess androgen and glucocorticoid production are the most common presentations of ACC. Other uncommon presentations include abdominal pain and adrenal incidentalomas. In the present report, a 71-year-old male presented with abdominal pain and was eventually diagnosed with ACC. He was found to have pulmonary thromboembolism following an investigation for hypoxemia, with the tumor thrombus extending upto the right atrium. This interesting case represents the unique presentation of a rare tumor, which if detected late or left untreated is associated with poor outcomes, highlighting the need for a low index of suspicion for ACC when similar presentations are encountered in clinical practice., Learning Points: ACC is a rare but aggressive tumor. ACC commonly presents with rapid onset of hypercortisolism, combined hyperandrogenism and hypercortisolism, or uncommonly with compressive symptoms. Clinicians should have a low index of suspicion for ACC in patients presenting with rapid onset of symptoms related to hypercortisolism and/or hyperandrogenism. Venous thromboembolism and extension of the tumor thrombus to the right side of the heart is a very rare but serious complication of ACC that clinicans should be wary of. The increased risk of venous thromboembolism in ACC could be explained by direct tumor invasion, tumor thrombi or hypercoagulability secondary to hypercortisolism. Early diagnosis and prompt treatment can improve the long-term survival of patients with ACC.

Fibrous dysplasia (FD) is a mosaic skeletal disorder resulting in fractures, deformity, and functional impairment. Clinical evaluation has been limited by a lack of surrogate endpoints capable of quantitating disease activity. The purpose of this study was to investigate the utility of 18 F-NaF PET/CT imaging in quantifying disease activity in patients with FD. Fifteen consecutively evaluated subjects underwent whole-body 18 F-NaF PET/CT scans, and FD burden was assessed by quantifying FD-related 18 F-NaF activity. 18 F-NaF PET/CT parameters obtained included (i) SUV max (standardized uptake value [SUV] of the FD lesion with the highest uptake); (ii) SUV mean (average SUV of all 18 F-NaF-positive FD lesions); (iii) total volume of all 18 F-NaF-positive FD lesions (TV); and (iv) total FD lesion activity determined as the product of TV multiplied by SUV mean (TA =  TV ×  SUV mean ) (TA). Skeletal outcomes, functional outcomes, and bone turnover markers were correlated with 18 F-NaF PET/CT parameters. TV and TA of extracranial FD lesions correlated strongly with skeletal outcomes including fractures and surgeries (p values ≤ 0.003). Subjects with impaired ambulation and scoliosis had significantly higher TV and TA values (P < 0.05), obtained from extracranial and spinal lesions, respectively. Craniofacial surgeries correlated with TV and TA of skull FD lesions (P < 0.001). Bone turnover markers, including alkaline phosphatase, N-telopeptides, and osteocalcin, were strongly correlated with TV and TA (P < 0.05) extracted from FD lesions in the entire skeleton. No associations were identified with SUV max or SUV mean . Bone pain and age did not correlate with 18 F-NaF PET/CT parameters. FD burden evaluated by 18 F-NaF-PET/CT facilitates accurate assessment of FD activity, and correlates quantitatively with clinically-relevant skeletal outcomes. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Background: Magnetic resonance imaging (MRI)-guided pulsed focused ultrasound combined with the infusion of microbubbles (pFUS+MB) induces transient blood-brain barrier opening (BBBO) in targeted regions. pFUS+MB, through the facilitation of neurotherapeutics' delivery, has been advocated as an adjuvant treatment for neurodegenerative diseases and malignancies. Sterile neuroinflammation has been recently described following pFUS+MB BBBO. In this study, we used PET imaging with [18F]-DPA714, a biomarker of translocator protein (TSPO), to assess for neuroinflammatory changes following single and multiple pFUS+MB sessions., Methods: Three groups of Sprague-Dawley female rats received MRI-guided pFUS+MB (Optison™; 5-8 × 10 7  MB/rat) treatments to the left frontal cortex and right hippocampus. Group A rats were sonicated once. Group B rats were sonicated twice and group C rats were sonicated six times on weekly basis. Passive cavitation detection feedback (PCD) controlled the peak negative pressure during sonication. We performed T1-weighted scans immediately after sonication to assess efficiency of BBBO and T2*-weighted scans to evaluate for hypointense voxels. [18F]DPA-714 PET/CT scans were acquired after the BBB had closed, 24 h after sonication in group A and within an average of 10 days from the last sonication in groups B and C. Ratios of T1 enhancement, T2* values, and [18F]DPA-714 percent injected dose/cc (%ID/cc) values in the targeted areas to the contralateral brain were calculated. Histological assessment for microglial activation/astrocytosis was performed., Results: In all groups, [18F]DPA-714 binding was increased at the sonicated compared to non-sonicated brain (%ID/cc ratios > 1). Immunohistopathology showed increased staining for microglial and astrocytic markers in the sonicated frontal cortex compared to contralateral brain and to a lesser extent in the sonicated hippocampus. Using MRI, we documented BBB disruption immediately after sonication with resolution of BBBO 24 h later. We found more T2* hypointense voxels with increasing number of sonications. In a longitudinal group of animals imaged after two and after six sonications, there was no cumulative increase of neuroinflammation on PET., Conclusion: Using [18F]DPA-714 PET, we documented in vivo neuroinflammatory changes in association with pFUS+MB. Our protocol (utilizing PCD feedback to minimize damage) resulted in neuroinflammation visualized 24 h post one sonication. Our findings were supported by immunohistochemistry showing microglial activation and astrocytosis. Experimental sonication parameters intended for BBB disruption should be evaluated for neuroinflammatory sequelae prior to implementation in clinical trials.

Although the idea of the personalization of patient care dates back to the time of Hippocrates, recent advances in diagnostic medical imaging and molecular medicine are gradually transforming healthcare services, by offering information and diagnostic tools enabling individualized patient management. Facilitating personalized / precision medicine requires taking into account multiple heterogenous parameters, such as sociodemographics, gene variability, environmental and lifestyle factors. Therefore, one of the most critical challenges in personalized medicine is the need to transform large, multi-modal data into decision support tools, capable of bridging the translational gap to the clinical setting. Towards these challenges, deep learning (DL) provides a novel approach, which enables obtaining or developing high-accuracy, multi-modal predictive models, that allow the implementation of the personalized medicine vision in the near future. DL is a highly effective strategy in addressing these challenges, with DL-based models leading to unprecedented results, matching or even improving state-of-the-art prediction/detection rates based on both intuitive and non-intuitive disease descriptors. These results hold promise for significant socio-economic benefits from the application of DL personalized medicine.

Melorheostosis is a rare hyperostotic disease of the long bones classically characterized by a "dripping candle-wax" radiographic appearance. We recently described somatic activating mutations in MAP2K1 as a cause of melorheostosis. Here, we report distinguishing characteristics of patients with MAP2K1-positive melorheostosis. Fifteen unrelated patients with radiographic appearance of melorheostosis underwent paired biopsies of affected and unaffected bone for whole-exome sequencing, histology, and cell culture. Eight patients with mutations in MAP2K1 in affected bone were compared to the seven MAP2K1-negative patients to identify distinguishing characteristics. Patients with MAP2K1-positive melorheostosis had a distinct phenotype with classic "dripping candle-wax" appearance on radiographs (p = 0.01), characteristic vascular lesions on skin overlying affected bone (p = 0.01), and higher prevalence of extraosseous mineralization and joint involvement (p = 0.04 for both). Melorheostotic bone from both MAP2K1-positive and MAP2K1-negative patients showed two zones of distinct morphology-an outer segment of parallel layers of primary lamellar bone and a deeper zone of intensely remodeled highly porous osteonal-like bone. Affected bone from MAP2K1-positive patients showed excessive osteoid (p = 0.0012), increased number of osteoblasts (p = 0.012) and osteoclasts (p = 0.04), and increased vascularity on histology in comparison to paired unaffected bone which was not seen in affected bone in most MAP2K1-negative patients. The identification of a distinct phenotype of patients with MAP2K1-positive melorheostosis demonstrates clinical and genetic heterogeneity among patients with the disease. Further studies are needed to better understand the underlying pathophysiology and associated skin findings. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Background & Aims: Survival times vary among patients with neuroendocrine tumors (NETs) - even among those with the same site, stage, and grade of primary tumor. This makes it difficult to select treatment for patients with unresectable NETs because some patients can survive decades without treatment. 68 Gallium-DOTATATE positron emission tomography with computed tomography ( 68 Ga-DOTATATE PET/CT) is a sensitive imaging technique for detection of NETs. We investigated the prognostic accuracy of 68 Ga-DOTATATE PET/CT-based analysis of tumor volume in patients with NETs., Methods: We performed a prospective study of 184 patients with NETs (128 [69.6%] with metastases and 11 patients [6.0%] with locally advanced disease) at the National Institutes of Health Clinical Center (Bethesda, MD) from 2013 through 2017. All patients underwent 68 Ga-DOTATATE PET/CT image analysis and total 68 Ga-DOTATATE-Avid tumor volume ( 68 Ga-DOTATATE TV) was determined. We also measured fasting serum chromogranin A, neuron-specific enolase, gastrin, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, and 24-hour urinary 5-hydroxyindoleacetic acid levels in all patients. Disease progression was defined as a new lesion or a growth of a known lesion during the interval between baseline 68 Ga-DOTATATE PET/CT scan and follow-up imaging (14.0 ± 6.1 months; range, 1-35 months). The primary outcomes were progression-free survival (PFS) and disease-specific mortality during a median follow-up time of 18 months (range, 4-35 months)., Results: We found an inverse correlation between quartiles of 68 Ga-DOTATATE TV and PFS (P = .001) and disease-specific survival (P = .002). A 68 Ga-DOTATATE TV of 7.0 mL or more was associated with higher odds of disease progression (hazard ratio, 3.0; P = .04). A 68 Ga-DOTATATE TV of 35.8 mL or more was associated with increased risk of disease-specific death (hazard ratio, 10.6) in multivariable analysis (P = .01), as well as in subgroup analysis of patients with pancreatic NETs., Conclusions: In a prospective study, we demonstrated the prognostic utility of 68 Ga-DOTATATE TV in a large cohort of patients with NETs, in terms of PFS and disease-specific mortality., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Unstable isotopes and their capacity to emit ionizing radiation have been employed in clinical practice not only for diagnostic, but also for therapeutic purposes, with significant contribution in several fields of medicine and primarily in the management of oncologic patients. Their efficacy is associated with their ability to provide the targeted delivery of ionizing radiation for a determined duration. These compounds can be used for curative or palliative treatment, as well as for a diagnostic-therapeutic (theranostic) approach. This review summarises the most recent trends in radionuclide treatment for several malignancies, including prostate cancer, neuroendocrine tumours, and hematological and thyroid malignancies, in which radionuclide-based therapies have been employed with high effectiveness.

We present a new image quality assessment method for determining whether reducing radiation dose impairs the image quality of computed tomography (CT) in qualitative and quantitative clinical analyses tasks. In this Institutional Review Board-exempt study, we conducted a review of 50 patients (male, 22; female, 28) who underwent reduced-dose CT scanning on the first follow-up after standard-dose multiphase CT scanning. Scans were for surveillance of von Hippel-Lindau disease (N = 26) and renal cell carcinoma (N = 10). We investigated density, morphometric, and structural differences between scans both at tissue (fat, bone) and organ levels (liver, heart, spleen, lung). To quantify structural variations caused by image quality differences, we propose using the following metrics: dice similarity coefficient, structural similarity index, Hausdorff distance, gradient magnitude similarity deviation, and weighted spectral distance. Pearson correlation coefficient and Welch 2-sample t test were used for quantitative comparisons of organ morphometry and to compare density distribution of tissue, respectively. For qualitative evaluation, 2-sided Kendall Tau test was used to assess agreement among readers. Both qualitative and quantitative evaluations were designed to examine significance of image differences for clinical tasks. Qualitative judgment served as an overall assessment, whereas detailed quantifications on structural consistency, intensity homogeneity, and texture similarity revealed more accurate and global difference estimations. Qualitative and quantitative results indicated no significant image quality degradation. Our study concludes that low(er)-dose CT scans can be routinely used because of no significant loss in quantitative image information compared with standard-dose CT scans.

In this paper, we investigate the automatic detection of white and brown adipose tissues using Positron Emission Tomography/Computed Tomography (PET/CT) scans, and develop methods for the quantification of these tissues at the whole-body and body-region levels. We propose a patient-specific automatic adiposity analysis system with two modules. In the first module, we detect white adipose tissue (WAT) and its two sub-types from CT scans: Visceral Adipose Tissue (VAT) and Subcutaneous Adipose Tissue (SAT). This process relies conventionally on manual or semi-automated segmentation, leading to inefficient solutions. Our novel framework addresses this challenge by proposing an unsupervised learning method to separate VAT from SAT in the abdominal region for the clinical quantification of central obesity. This step is followed by a context driven label fusion algorithm through sparse 3D Conditional Random Fields (CRF) for volumetric adiposity analysis. In the second module, we automatically detect, segment, and quantify brown adipose tissue (BAT) using PET scans because unlike WAT, BAT is metabolically active. After identifying BAT regions using PET, we perform a co-segmentation procedure utilizing asymmetric complementary information from PET and CT. Finally, we present a new probabilistic distance metric for differentiating BAT from non-BAT regions. Both modules are integrated via an automatic body-region detection unit based on one-shot learning. Experimental evaluations conducted on 151 PET/CT scans achieve state-of-the-art performances in both central obesity as well as brown adiposity quantification.

Competing Interests: None

The authors describe the clinical investigation and progress of a 13-year-old girl diagnosed with hypertension 4 years prior to her admission. A thorough history was taken and physical examination performed. Laboratory analysis and relevant radiological evaluation were obtained in order to determine the etiology for suspected secondary hypertension, and later to differentiate between the possible causes of hyperreninemic hypertension. The patient had an accessory left renal artery, presumptively leading to renin secretion by the underperfused kidney. The patient was treated medically with spontaneous resolution of her hypertension and near normalization of plasma renin activity. On repeat imaging, the artery was not demonstrated. The authors concluded that the diagnosis of hyperreninemic hypertension in young ages should prompt investigation for the etiology. However, cautious observation is a valid option that might lead to spontaneous resolution., (Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)

Carney complex (CNC) is a multiple neoplasia syndrome that is caused mostly by PRKAR1A mutations. Cardiac myxomas are the leading cause of mortality in CNC patients who, in addition, often develop growth hormone (GH) excess. We studied patients with CNC, who were observed for over a period of 20 years (1995-2015) for the development of both GH excess and cardiac myxomas. GH secretion was evaluated by standard testing; dedicated cardiovascular imaging was used to detect cardiac abnormalities. Four excised cardiac myxomas were tested for the expression of insulin-like growth factor-1 (IGF-1). A total of 99 CNC patients (97 with a PRKAR1A mutation) were included in the study with a mean age of 25.8 ± 16.6 years at presentation. Over an observed mean follow-up of 25.8 years, 60% of patients with GH excess (n = 46) developed a cardiac myxoma compared with only 36% of those without GH excess (n = 54) (P = 0.016). Overall, patients with GH excess were also more likely to have a tumor vs those with normal GH secretion (OR: 2.78, 95% CI: 1.23-6.29; P = 0.014). IGF-1 mRNA and protein were higher in CNC myxomas than in normal heart tissue. We conclude that the development of cardiac myxomas in CNC may be associated with increased GH secretion, in a manner analogous to the association between fibrous dysplasia and GH excess in McCune-Albright syndrome, a condition similar to CNC. We speculate that treatment of GH excess in patients with CNC may reduce the likelihood of cardiac myxoma formation and/or recurrence of this tumor., (© 2016 Society for Endocrinology.)

Background: Thyroid cancer is the most common endocrine gland malignancy. Advances in understanding the genetic basis for thyroid cancer revealed the potential involvement of several genes in the formation of thyroid tumors. Mutations in the gene coding for succinate dehydrogenase subtype B (SDHB) have been implicated in papillary thyroid cancer (PTC). Succinate dehydrogenase (SDH) is a heterotetrameric protein composed of four subunits, SDHA, SDHB, SDHC, and SDHD, and participates in both the electron transport chain and the tricarboxylic acid cycle. The aim of the study was to evaluate the association between variants in the SDHA, SDHB, SDHC, and SDHD genes and familiar PTC in a large Brazilian family., Method: Four patients with PTC, 1 patient with PTC and gastrointestinal stromal tumor (GIST), 1 patient with GIST, and their relatives - several of them with different thyroid problems - from a large Brazilian family were screened for genetic variations of SDHx genes with the use of polymerase chain reaction-single-stranded conformational polymorphism and direct sequencing., Results: Only one rare variation in SDHA was found in some of the family members, but not segregating with the disease. No other genetic variants of these genes were detected in the family members that presented with PTC and/or GIST., Conclusion: Familiar PTC and a GIST were not associated with SDHx mutations; additional genetic defects, yet unknown, may be responsible for the development of tumor.

Motor and behavioral abnormalities are common presentations among individuals with HIV-1 associated neurocognitive disorders (HAND). We investigated whether longitudinal motor and behavioral performance in the HIV-1 transgenic rat (Tg), a commonly used neuro-HIV model, corresponded to in vivo neuronal death/dysfunction, by using rotarod and open field testing in parallel to [18F] 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). We demonstrated that age-matched non-Tg wild type (WT) rats outperformed the HIV-1 Tg rats at most time points on rotarod testing. Habituation to rotarod occurred at 8 weeks of age (fifth weekly testing session) in the WT rats but it never occurred in the Tg rats, suggesting deficits in motor learning. Similarly, in open field testing, WT rats outperformed the Tg rats at most time points, suggesting defective exploratory/motor behavior and increased emotionality in the Tg rat. Despite the neurobehavioral abnormalities, there were no concomitant deficits in 18F-FDG uptake in Tg rats on PET compared to age-matched WT rats and no significant longitudinal loss of FDG uptake in either group. The negative PET findings were confirmed using 14C- Deoxy-D-glucose autoradiography in 32 week-old Tg and WT rats. We believe that the neuropathology in the HIV-1 Tg rat is more likely a consequence of neuronal dysfunction rather than overt neurodegeneration/neuronal cell death, similar to what is seen in HIV-positive patients in the post-ART era.

Background: A high prevalence of osteopenia and osteoporosis is observed in patients with inflammatory bowel disease (IBD). Various risk factors of bone loss have been suggested in IBD. The aim of the present study was to investigate the prevalence of low bone mineral density (BMD) and to identify related risk factors in Greek patients with IBD., Methods: One hundred and eighteen consecutive IBD patients were included. All patients underwent bone densitometry by dual energy X-ray absorptiometry at the femoral neck and lumbar spine levels. Serum levels of 25 hydroxyvitamin D (25 OH D), 1.25 dihydroxyvitamin D (1.25 OH 2D), osteocalcin, calcitonin and homocysteine were measured in all participants., Results: Forty (33.9%) patients were normal, 55 (46.6%) were osteopenic, and 23 (19.5%) were osteoporotic. No significant differences between IBD patients with osteopenia or osteoporosis and those with normal BMD concerning the use of steroids and the examined biochemical markers were found. Statistically significant differences among the three groups were found for body mass index (BMI), age and disease duration (P=0.002, P<0.0001 and P=0.03 respectively). Multivariate analysis revealed that the most significant factors associated with BMD were age and BMI (P<0.0001). A weak but statistically significant correlation was also found for disease duration (P=0.04)., Conclusions: There is a high prevalence of osteopenia and osteoporosis in Greek patients with IBD. Low BMI, age and disease duration are the most important independent risk factors for osteoporosis in Greek IBD patients.