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Accurate coregistration of computed tomography (CT) and magnetic resonance (MR) imaging can provide clinically relevant and complementary information and can serve to facilitate multiple clinical tasks including surgical and radiation treatment planning, and generating a virtual Positron Emission Tomography (PET)/MR for the sites that do not have a PET/MR system available. Despite the long-standing interest in multimodality co-registration, a robust, routine clinical solution remains an unmet need. Part of the challenge may be the use of mutual information (MI) maximization and local phase difference (LPD) as similarity metrics, which have limited robustness, efficiency, and are difficult to optimize. Accordingly, we propose registering MR to CT by mapping the MR to a synthetic CT intermediate (sCT) and further using it in a sCT-CT deformable image registration (DIR) that minimizes the sum of squared differences. The resultant deformation field of a sCT-CT DIR is applied to the MRI to register it with the CT. Twenty-five sets of abdominopelvic imaging data are used for evaluation. The proposed method is compared to standard MI- and LPD-based methods, and the multimodality DIR provided by a state of the art, commercially available FDA-cleared clinical software package. The results are compared using global similarity metrics, Modified Hausdorff Distance, and Dice Similarity Index on six structures. Further, four physicians visually assessed and scored registered images for their registration accuracy. As evident from both quantitative and qualitative evaluation, the proposed method achieved registration accuracy superior to LPD- and MI-based methods and can refine the results of the commercial package DIR when using its results as a starting point. Supported by these, this manuscript concludes the proposed registration method is more robust, accurate, and efficient than the MI- and LPD-based methods.

Computed tomography (CT) provides information for diagnosis, PET attenuation correction (AC), and radiation treatment planning (RTP). Disadvantages of CT include poor soft tissue contrast and exposure to ionizing radiation. While MRI can overcome these disadvantages, it lacks the photon absorption information needed for PET AC and RTP. Thus, an intelligent transformation from MR to CT, i.e., the MR-based synthetic CT generation, is of great interest as it would support PET/MR AC and MR-only RTP. Using an MR pulse sequence that combines ultra-short echo time (UTE) and modified Dixon (mDixon), we propose a novel method for synthetic CT generation jointly leveraging prior knowledge as well as partial supervision (SCT-PK-PS for short) on large-field-of-view images that span abdomen and pelvis. Two key machine learning techniques, i.e., the knowledge-leveraged transfer fuzzy c-means (KL-TFCM) and the Laplacian support vector machine (LapSVM), are used in SCT-PK-PS. The significance of our effort is threefold: 1) Using the prior knowledge-referenced KL-TFCM clustering, SCT-PK-PS is able to group the feature data of MR images into five initial clusters of fat, soft tissue, air, bone, and bone marrow. Via these initial partitions, clusters needing to be refined are observed and for each of them a few additionally labeled examples are given as the partial supervision for the subsequent semi-supervised classification using LapSVM; 2) Partial supervision is usually insufficient for conventional algorithms to learn the insightful classifier. Instead, exploiting not only the given supervision but also the manifold structure embedded primarily in numerous unlabeled data, LapSVM is capable of training multiple desired tissue-recognizers; 3) Benefiting from the joint use of KL-TFCM and LapSVM, and assisted by the edge detector filter based feature extraction, the proposed SCT-PK-PS method features good recognition accuracy of tissue types, which ultimately facilitates the good transformation from MR images to CT images of the abdomen-pelvis. Applying the method on twenty subjects' feature data of UTE-mDixon MR images, the average score of the mean absolute prediction deviation (MAPD) of all subjects is 140.72 ± 30.60 HU which is statistically significantly better than the 241.36 ± 21.79 HU obtained using the all-water method, the 262.77 ± 42.22 HU obtained using the four-cluster-partitioning (FCP, i.e., external-air, internal-air, fat, and soft tissue) method, and the 197.05 ± 76.53 HU obtained via the conventional SVM method. These results demonstrate the effectiveness of our method for the intelligent transformation from MR to CT on the body section of abdomen-pelvis.

PURPOSE: Accurate photon attenuation assessment from MR data remains an unmet challenge in the thorax due to tissue heterogeneity and the difficulty of MR lung imaging. As thoracic tissues encompass the whole physiologic range of photon absorption, large errors can occur when using, for example, a uniform, water‐equivalent or a soft‐tissue‐only approximation. The purpose of this study was to introduce a method for voxel‐wise thoracic synthetic CT (sCT) generation from MR data attenuation correction (AC) for PET/MR or for MR‐only radiation treatment planning (RTP). METHODS: Acquisition: A radial stack‐of‐stars combining ultra‐short‐echo time (UTE) and modified Dixon (mDixon) sequence was optimized for thoracic imaging. The UTE‐mDixon pulse sequence collects MR signals at three TE times denoted as UTE, Echo1, and Echo2. Three‐point mDixon processing was used to reconstruct water and fat images. Bias field correction was applied in order to avoid artifacts caused by inhomogeneity of the MR magnetic field. Analysis: Water fraction and R2* maps were estimated using the UTE‐mDixon data to produce a total of seven MR features, that is UTE, Echo1, Echo2, Dixon water, Dixon fat, Water fraction, and R2*. A feature selection process was performed to determine the optimal feature combination for the proposed automatic, 6‐tissue classification for sCT generation. Fuzzy c‐means was used for the automatic classification which was followed by voxel‐wise attenuation coefficient assignment as a weighted sum of those of the component tissues. Performance evaluation: MR data collected using the proposed pulse sequence were compared to those using a traditional two‐point Dixon approach. Image quality measures, including image resolution and uniformity, were evaluated using an MR ACR phantom. Data collected from 25 normal volunteers were used to evaluate the accuracy of the proposed method compared to the template‐based approach. Notably, the template approach is applicable here, that is normal volunteers, but may not be robust enough for patients with pathologies. RESULTS: The free breathing UTE‐mDixon pulse sequence yielded images with quality comparable to those using the traditional breath holding mDixon sequence. Furthermore, by capturing the signal before T2* decay, the UTE‐mDixon image provided lung and bone information which the mDixon image did not. The combination of Dixon water, Dixon fat, and the Water fraction was the most robust for tissue clustering and supported the classification of six tissues, that is, air, lung, fat, soft tissue, low‐density bone, and dense bone, used to generate the sCT. The thoracic sCT had a mean absolute difference from the template‐based (reference) CT of less than 50 HU and which was better agreement with the reference CT than the results produced using the traditional Dixon‐based data. CONCLUSION: MR thoracic acquisition and analyses have been established to automatically provide six distinguishable tissue types to generate sCT for MR‐based AC of PET/MR and for MR‐only RTP.

Oligometastatic non-small cell lung cancer (NSCLC) is an intermediate state between localized and widely metastatic NSCLC, where systemic therapy in combination with aggressive local therapy when feasible can yield a favorable outcome. While different societies have adopted different definitions for oligometastatic NSCLC, the feasibility of curative intent treatment remains a major determinant of the oligometastatic state. The management involves a multidisciplinary approach to identify such patients with oligometastatic stage, including the presence of symptomatic or potentially symptomatic brain metastasis, the presence of targetable mutations, and programmed death-ligand (PD-L1) expression. Treatment requires a personalized approach with the use of novel systemic agents such as tyrosine kinase inhibitors and immune checkpoint inhibitors with or without chemotherapy, and addition of local ablative therapy via surgery or stereotactic radiation therapy when appropriate.

Purpose/objective(s) Stereotactic body radiation therapy (SBRT) has emerged as an effective treatment approach in oligometastatic patients with adrenal gland metastases (AGM). Nevertheless, most of the literature reporting SBRT outcomes for AGM comes from published single institutional experience, and no specific guidelines are yet established to guide patients' inclusion and dosimetric planning. Materials/methods The Consortium for Oligometastases Research (CORE) is currently the largest retrospective series of patients with oligometastases (OM). Among CORE patients, those treated with SBRT for AGM were included. Adrenal metastatic burden (AMB) was defined as the sum of all adrenal GTV if more than one OM is present. BED10 was calculated with tumor alpha/beta ratio of 10. Competing risk analysis was used to estimate the risk of local recurrence (LR) and widespread progression (WP) over time, using death from any cause as a competing risk factor. Kaplan-Meier method was used to estimate the overall survival (OS), local recurrence-free survival (LRFS), and progression-free survival (PFS). Univariable and multivariable regression was used to quantify the relationship between potential predictors and the main endpoints. A P-value threshold of 0.05 was used for statistical significance. Results 46 patients with 57 adrenal lesions were included. Median follow-up was 18.2 months. The most common primary malignancy was NSCLC. The mean (standard deviation) age at diagnosis was 65.84 (10.84) years, with 25 (53.2%) male patients and 22 (46.8%) female patients. 8 out of the 46 patients had developed more than one AGM. The most used fractionation scheme was 30 - 35 Gy in 3 - 5 fractions, and the mean prescribed BED10 was 69.37 Gy10. Median LRFS, PFS, and OS were 15.3, 5.29, and 19.1 months, respectively. The 1-year and 5-year LRFS were 65% and 25.4%, respectively. The 1-year and 5-year OS were 70% and 33%, respectively. Only 1 patient developed a Grade 3 GI toxicity. On multivariable regression, a minimum received PTV dose > 46 Gy10 was associated with an improved OS (HR 0.42, 95% CI [0.20 - 0.89], P = 0.024) and LRFS (HR 0.37, [0.18 - 0.76], P = 0.006), after adjusting for primary site. A prescribed BED10 more than 70 Gy10 was an independent prognostic factor of a lower LR rate (HR 0.31, [0.102-0.94], P = 0.039). Interestingly, AMB greater than 10 cc was an independent predictor of a lower risk WP (HR 0.29, [0.11 - 0.80], P = 0.017), after adjusting for primary histology and number of OM. Conclusion SBRT to AGM is a safe procedure that achieves a satisfactory local control and survival in oligometastatic patients. The current results suggest that patients should be treated with a prescription BED10 dose of at least 70 Gy10, and a minimum PTV dose > 46 Gy10, if safely achievable. Paradoxically, AMB > 10cc was favorable, and a high AMB should not preclude the administration of a definitive course of SBRT. Prospective studies are needed to determine comprehensive criteria for patients SBRT eligibility and dosimetric planning.

Aim: This systematic review summarizes the clinical data on focal therapy (FT) when used alone as definitive therapy for primary prostate cancer (PCa). Methods: The protocol is detailed in the online PROSPERO database, registration No. CRD42014014765. Articles evaluating any form of FT alone as a definitive treatment for PCa in adult male patients were included. Results: Of 10,419 identified articles, 10,401 were excluded, and thus leaving 18 for analysis. In total, 2288 patients were treated using seven modalities. The outcomes of FT in PCa seem to be similar to those observed with whole gland therapy and with fewer side effects. Conclusion: Further research, including prospective randomized trials, is warranted to elucidate the potential advantages of focal radiation techniques for treating PCa. Prospero Registration Number: CRD42014014765.

We propose a new method for generating synthetic CT images from modified Dixon (mDixon) MR data. The synthetic CT is used for attenuation correction (AC) when reconstructing PET data on abdomen and pelvis. While MR does not intrinsically contain any information about photon attenuation, AC is needed in PET/MR systems in order to be quantitatively accurate and to meet qualification standards required for use in many multi-center trials. Existing MR-based synthetic CT generation methods either use advanced MR sequences that have long acquisition time and limited clinical availability or use matching of the MR images from a newly scanned subject to images in a library of MR-CT pairs which has difficulty in accounting for the diversity of human anatomy especially in patients that have pathologies. To address these deficiencies, we present a five-phase interlinked method that uses mDixon MR acquisition and advanced machine learning methods for synthetic CT generation. Both transfer fuzzy clustering and active learning-based classification (TFC-ALC) are used. The significance of our efforts is fourfold: 1) TFC-ALC is capable of better synthetic CT generation than methods currently in use on the challenging abdomen using only common Dixon-based scanning. 2) TFC partitions MR voxels initially into the four groups regarding fat, bone, air, and soft tissue via transfer learning; ALC can learn insightful classifiers, using as few but informative labeled examples as possible to precisely distinguish bone, air, and soft tissue. Combining them, the TFC-ALC method successfully overcomes the inherent imperfection and potential uncertainty regarding the co-registration between CT and MR images. 3) Compared with existing methods, TFC-ALC features not only preferable synthetic CT generation but also improved parameter robustness, which facilitates its clinical practicability. Applying the proposed approach on mDixon-MR data from ten subjects, the average score of the mean absolute prediction deviation (MAPD) was 89.78±8.76 which is significantly better than the 133.17±9.67 obtained using the all-water (AW) method (p=4.11E-9) and the 104.97±10.03 obtained using the four-cluster-partitioning (FCP, i.e., external-air, internal-air, fat, and soft tissue) method (p=0.002). 4) Experiments in the PET SUV errors of these approaches show that TFC-ALC achieves the highest SUV accuracy and can generally reduce the SUV errors to 5% or less. These experimental results distinctively demonstrate the effectiveness of our proposed TFC-ALC method for the synthetic CT generation on abdomen and pelvis using only the commonly-available Dixon pulse sequence.

Background Manual contouring for radiation therapy planning remains the most laborious and time consuming part in the radiation therapy workflow. Particularly for cervical cancer, this task is complicated by the complex female pelvic anatomy and the concomitant dependence on 18F-labeled Fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance (MR) images. Using deep learning, we propose a new auto-contouring method for FDG-PET/MR based cervical cancer radiation therapy by combining the high level anatomical topography and radiological properties, to the low-level pixel wise deep-learning based semantic segmentation. Materials/methods The proposed method: 1) takes advantage of PET data and left/right anatomical symmetry, creating sub-volumes that are centered on the structures to be contoured. 2) Uses a 3D shallow U-Net (sU-Net) model with an encoder depth of 2.3) Applies the successive training of 3 consecutive sU-Nets in a feed forward strategy. 4) Employs, instead of the usual generalized dice loss function (GDL), a patch dice loss function (PDL) that takes into account the Dice similarity index (DSI) at the level of each training patch. Experimental analysis was conducted on a set of 13 PET/MR images was using a leave-one-out strategy. Results Despite the limited data availability, 5 anatomical structures - the gross tumor volume, bladder, anorectum, and bilateral femurs - were accurately (DSI ​= ​0.78), rapidly (1.9 ​s/structure), and automatically delineated by our algorithm. Overall, PDL achieved a better performance than GDL and DSI was higher for organs at risk (OARs) with solid tissue (e.g. femurs) than for OARs with air-filled soft tissues (e.g. anorectum). Conclusion The presented workflow successfully addresses the challenge of auto-contouring in FDG-PET/MR based cervical cancer. It is expected to expedite the cervical cancer radiation therapy workflow in both, conventional and adaptive radiation therapy settings.

Purpose Generation of synthetic Computed Tomography (sCT) images from Magnetic Resonance (MR) is an imperative, yet not fully resolved task for attenuation correction in Positron Emission Tomography (PET)/MR and treatment planning in MR-only radiation therapy. Herein, we propose a Generative Adversarial Networks (GAN) model to generate quantitatively accurate sCT from Dixon thorax MR data. Materials/methods Paired image sets of Dixon MR and corresponding CT volumes from fourteen subjects were used. In-phase (IP) MR images were registered to the CT images using REGGUI. The resulting deformation field was applied to the three other [opposed-phase (OP), fat, water] MR images. Image processing was implemented in MATLAB 2016b (MathWorks) using COMKAT Image Tool. Manual contouring was performed on the CT images using MIM (version 6.6.10, MIM Software Inc., Cleveland, OH) software, to delineate the left lung, right lung, vertebral body, and spinal cord. The proposed RU-cGAN model incorporates R esNet and U-Net in the generator of a c onditional G AN. Results from Vgg16, Vgg19, and ResNet were used as references for comparison. The four networks were trained using two strategies. In the first, the four Dixon MR images were used as input features. In the second strategy, only fat and water images were used. Results Regardless of whether the input consists of two or four images types, sCT generated using RU- cGAN had the best agreement with the measured CT for all the metrics, having Mean Absolute Prediction Error (MAPE) ​ Conclusion RU-cGAN provides a rapid and accurate method for thorax sCT generation while obviating the bone-specific UTE pulse sequence and only requiring limited training data.

Cryptosporidium parvum is a major cause of diarrheal illness and was recently potentially associated with digestive carcinogenesis. Despite its impact on human health, Cryptosporidium pathogenesis remains poorly known, mainly due to the lack of a long-term culture method for this parasite. Thus, the aim of the present study was to develop a three-dimensional (3D) culture model from adult murine colon allowing biological investigations of the host-parasite interactions in an in vivo-like environment and, in particular, the development of parasite-induced neoplasia. Colonic explants were cultured and preserved ex vivo for 35 days and co-culturing was performed with C. parvum. Strikingly, the resulting system allowed the reproduction of neoplastic lesions in vitro at 27 days post-infection (PI), providing new evidence of the role of the parasite in the induction of carcinogenesis. This promising model could facilitate the study of host-pathogen interactions and the investigation of the process involved in Cryptosporidium-induced cell transformation.

Special attention is required in planning and administering radiation therapy to patients with cardiac implantable electronic devices (CIEDs), such as pacemaker and defibrillator. The range of dose to CIEDs that can induce malfunction is large among CIEDs. Clinically significant defects have been reported at dose as low as 0.15 Gy. Therefore, accurate estimation of dose to CIED and dose reduction are both important even if the dose is expected to be less than the often‐used 2‐Gy limit. We investigated the use of bolus in in vivo dosimetry for CIEDs. Solid water phantom measurements of out‐of‐field dose for a 6‐MV beam were performed using parallel plate chamber with and without 1‐ to 2‐cm bolus covering the chamber. In vivo dosimetry at skin surface above the CIED was performed with and without bolus covering the CIED for three patients with the CIED

Objective Right heart failure is associated with increased mortality and morbidity. The optimal treatment for patients with RV failure is not established. The aim of this study is to conduct a systematic review of the literature to assess the relative benefits and harms of digoxin therapy in patients with RV failure. Methods We performed a literature search in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) on Nov. 4, 2014. We did not use publication type, period or language restrictions to the search strategy. Exclusions included: trials that excluded patients with RV failure, included patients requiring mechanical or intravenous inotropic support, review papers and case reports. The primary outcome was long-term efficacy outcomes of digoxin in right heart failure. Two reviewers screened titles and abstracts of identified citations independently and in duplication using calibration exercises and standardized screening forms. Results The search strategy identified 4097 citations, and 4 studies were included in this analysis (n=76 patients). Of the four studies, two assessed improvements in RVEF, two studies compared exercise capacity indexes, and one assessed symptoms with digoxin compared with placebo. No study assessed mortality outcomes. Overall, there was no statistically significant improvement in RVEF, exercise capacity, NYHA class, heart failure score, or body weight. Conclusions There are few studies evaluating Digitalis use for RV failure, which are limited to patients with cor pulmonale. In these patients, Digitalis use provides no improvement in RVEF, exercise capacity, or NYHA class. Randomized clinical trials are needed to address this question.

Celiac disease, an autoimmune disease once thought to be uncommon, is now being increasingly identified. Our improved diagnostic modalities have allowed us to diagnose more and more patients with atypical symptoms who improve on gluten-free diet (GFD). We discuss here the latest findings regarding the various hematological manifestations of celiac disease and their management. Anemia remains the most common hematological manifestation of celiac disease due to many mechanisms, and can be the sole presenting symptom. Other manifestations include thrombocytosis and thrombocythemia, leukopenia, thromboembolism, increased bleeding tendency, IgA deficiency, splenic dysfunction, and lymphoma. The diagnosis of celiac disease should always be kept in mind when a patient presents with unexplained and isolated hematological finding. Once diagnosed, patients should adhere to GFD and be educated about the potential complications of this disease. We herein present an algorithm for adequate management and follow-up.

Background: Conflicting evidence exists on the ideal choice of non-invasive pharmacologic stress imaging for coronary artery disease (CAD) diagnosis in patients with left bundle branch block (LBBB). The aim of this meta-analysis is to compare data that examine the sensitivity and specificity of non-invasive pharmacologic stress imaging in patients with LBBB for obstructive CAD diagnosis. Methods: We performed a literature search in MEDLINE, embase.com and Cochrane (CENTRAL) without publication type or language restrictions. Both pharmacologic stress echocardiography (SE) and nuclear myocardial perfusion imaging (MPI) searches were restricted to the period between January 2004 and review time. Exclusion criteria included studies that lacked sensitivity and specificity data. The primary objective was to compare the sensitivities and specificities of all pharmacologic SE, MPI, myocardial contrast echocardiography (MCE), stress cardiac magnetic resonance (CMR) and positron emission tomography (PET) for identifying significant CAD in patients with LBBB. Results: 10 studies met the inclusion criteria for analysis. The sensitivity and specificity odds ratio of MCE was 92% (95% CI 81-97%), 93% (95% CI 86- 97%); Dobutamine (D)-CMR 64% (95% CI 42-82%), 94% (95% CI 85-98%); pharmacologic SE 73% (95% CI 55-86%), 84% (95% CI 75-91%); and pharmacologic MPI 83% (95% CI 72-91%), 56% (95% CI 42-70%). Conclusion: MCE and D-CMR appear to have improved diagnostic accuracy in comparison to pharmacologic SE and MPI in patients with LBBB. Additional MCE and D-CMR studies are warranted given their potential to become the non-invasive gold standard for the diagnosis of CAD in this population.

Aneurysmal dilation of a saphenous vein aortocoronary graft remains a rare complication. We report a patient with saphenous vein graft aneurysm who presented with abdominal pain due to compression of the adjacent liver 43 years after the coronary bypass operation.

Background Hospital-based palliative care programs in Lebanon are nonexistent in a structured form. One of obstacles is the lack of knowledge about symptom prevalence and burden of cancer patients in Lebanon. Methods This is a cross-sectional observational study where 100 adult cancer patients admitted to the American University of Beirut Medical Center inpatient unit completed a survey to assess 20 physical symptoms according the National Cancer Institute's Common Terminology Criteria for Adverse Events 4.0 (NCI-CTCAE 4.0) guidelines. Results Hematologic, gastrointestinal, breast, and lung cancers were the most common. Mean age was 51.5 years; 51% were female. 74% of patients with solid tumors had metastatic disease. Treatment approaches were palliative chemotherapy, followed by curative chemotherapy and best supportive care. The most common symptoms were fatigue, appetite loss, nausea, and pain; most distressing were nausea, pain, and fatigue. Nausea and vomiting were more prevalent among females than males. Females reported more severe vomiting than males, but males had more intense pain. Overall symptom burden difference was statistically significant across age groups, with the 51–60 year group having the most symptoms, but not among different genders. Difference was significant among different treatment intents, with the best supportive care group having most symptoms. Conclusion Fatigue should be better addressed as a legitimate symptom. Subgroup differences must be considered when managing gastrointestinal symptoms. Pain should be more effectively managed, and vulnerable subgroups such as the 51–60 year age group and those on best supportive care should receive special consideration.