Artificial Intelligence for Quantifying Cumulative Small Bowel Disease Severity on CT-Enterography in Crohn's Disease.

INTRODUCTION: Assessing the cumulative degree of bowel injury in ileal Crohn's disease (CD) is difficult. We aimed to develop machine learning (ML) methodologies for automated estimation of cumulative ileal injury on computed tomography-enterography (CTE) to help predict future bowel surgery. METHODS: Adults with ileal CD using biologic therapy at a tertiary care center underwent ML analysis of CTE scans. Two fellowship-trained radiologists graded bowel injury severity at granular spatial increments along the ileum (1 cm), called mini-segments. ML segmentation methods were trained on radiologist grading with predicted severity and then spatially mapped to the ileum. Cumulative injury was calculated as the sum (S-CIDSS) and mean of severity grades along the ileum. Multivariate models of future small bowel resection were compared with cumulative ileum injury metrics and traditional bowel measures, adjusting for laboratory values, medications, and prior surgery at the time of CTE. RESULTS: In 229 CTE scans, 8,424 mini-segments underwent analysis. Agreement between ML and radiologists injury grading was strong (κ = 0.80, 95% confidence interval 0.79-0.81) and similar to inter-radiologist agreement (κ = 0.87, 95% confidence interval 0.85-0.88). S-CIDSS (46.6 vs 30.4, P = 0.0007) and mean cumulative injury grade scores (1.80 vs 1.42, P < 0.0001) were greater in CD biologic users that went to future surgery. Models using cumulative spatial metrics (area under the curve = 0.76) outperformed models using conventional bowel measures, laboratory values, and medical history (area under the curve = 0.62) for predicting future surgery in biologic users. DISCUSSION: Automated cumulative ileal injury scores show promise for improving prediction of outcomes in small bowel CD. Beyond replicating expert judgment, spatial enterography analysis can augment the personalization of bowel assessment in CD.

Independent Associations of Aortic Calcification with Cirrhosis and Liver Related Mortality in Veterans with Chronic Liver Disease.

INTRODUCTION: Abdominal aortic calcifications (AAC) are incidentally found on medical imaging and useful cardiovascular burden approximations. The Morphomic Aortic Calcification Score (MAC) leverages automated deep learning methods to quantify and score AACs. While associations of AAC and non-alcoholic fatty liver disease (NAFLD) have been described, relationships of AAC with other liver diseases and clinical outcome are sparse. This study's purpose was to evaluate AAC and liver-related death in a cohort of Veterans with chronic liver disease (CLD). METHODS: We utilized the VISN 10 CLD cohort, a regional cohort of Veterans with the three forms of CLD: NAFLD, hepatitis C (HCV), alcohol-associated (ETOH), seen between 2008 and 2014, with abdominal CT scans (n = 3604). Associations between MAC and cirrhosis development, liver decompensation, liver-related death, and overall death were evaluated with Cox proportional hazard models. RESULTS: The full cohort demonstrated strong associations of MAC and cirrhosis after adjustment: HR 2.13 (95% CI 1.63, 2.78), decompensation HR 2.19 (95% CI 1.60, 3.02), liver-related death HR 2.13 (95% CI 1.46, 3.11), and overall death HR 1.47 (95% CI 1.27, 1.71). These associations seemed to be driven by the non-NAFLD groups for decompensation and liver-related death [HR 2.80 (95% CI 1.52, 5.17; HR 2.34 (95% CI 1.14, 4.83), respectively]. DISCUSSION: MAC was strongly and independently associated with cirrhosis, liver decompensation, liver-related death, and overall death. Surprisingly, stratification results demonstrated comparable or stronger associations among those with non-NAFLD etiology. These findings suggest abdominal aortic calcification may predict liver disease severity and clinical outcomes in patients with CLD.

Sarcopenia provides extra value outside the PULP score for predicting mortality in older patients with perforated peptic ulcers.

BACKGROUND: Perforated peptic ulcer (PPU) remains challenging surgically due to its high mortality, especially in older individuals. Computed tomography (CT)-measured skeletal muscle mass is a effective predictor of the surgical outcomes in older patients with abdominal emergencies. The purpose of this study is to assess whether a low CT-measured skeletal muscle mass can provide extra value in predicting PPU mortality. METHODS: This retrospective study enrolled older (aged ≥ 65 years) patients who underwent PPU surgery. Cross-sectional skeletal muscle areas and densities were measured by CT at L3 and patient-height adjusted to obtain the L3 skeletal muscle gauge (SMG). Thirty-day mortality was determined with univariate, multivariate and Kaplan-Meier analysis. RESULTS: From 2011 to 2016, 141 older patients were included; 54.8% had sarcopenia. They were further categorized into the PULP score ≤ 7 (n=64) or PULP score > 7 group (n=82). In the former, there was no significant difference in 30-day mortality between sarcopenic (2.9%) and nonsarcopenic patients (0%; p=1.000). However, in the PULP score > 7 group, sarcopenic patients had a significantly higher 30-day mortality (25.5% vs. 3.2%, p=0.009) and serious complication rate (37.3% vs. 12.9%, p=0.017) than nonsarcopenic patients. Multivariate analysis showed that sarcopenia was an independent risk factor for 30-day mortality in patients in the PULP score > 7 group (OR: 11.05, CI: 1.03-118.7). CONCLUSION: CT scans can diagnose PPU and provide physiological measurements. Sarcopenia, defined as a low CT-measured SMG, provides extra value in predicting mortality in older PPU patients.

Muscle mass affects paclitaxel systemic exposure and may inform personalized paclitaxel dosing.

AIMS: Patients with low muscle mass have increased risk of paclitaxel-induced peripheral neuropathy, which is dependent on systemic paclitaxel exposure. Dose optimization may be feasible through the secondary use of radiologic data for body composition. The objective of this study was to interrogate morphomic parameters as predictors of paclitaxel pharmacokinetics to identify alternative dosing strategies that may improve treatment outcomes. METHODS: This was a secondary analysis of female patients with breast cancer scheduled to receive 80 mg/m2 weekly paclitaxel infusions. Paclitaxel was measured at the end of initial infusion to estimate maximum concentration (Cmax ). Computed tomography (CT) scans were used to measure 29 body composition features for inclusion in pharmacokinetic modelling. Monte Carlo simulations were performed to identify infusion durations that limit the probability of exceeding Cmax > 2885 ng/mL, which was selected based on prior work linking this to an unacceptable risk of peripheral neuropathy. RESULTS: Thirty-nine patients were included in the analysis. The optimal model was a two-compartment pharmacokinetic model with T11 skeletal muscle area as a covariate of paclitaxel volume of distribution (Vd). Simulations suggest that extending infusion of the standard paclitaxel dose from 1 hour to 2 and 3 hours in patients who have skeletal muscle area 4907-7080 mm2 and <4907 mm2 , respectively, would limit risk of Cmax > 2885 ng/mL to <50%, consequently reducing neuropathy, while marginally increasing overall systemic paclitaxel exposure. CONCLUSION: Extending paclitaxel infusion duration in ~25% of patients who have low skeletal muscle area is predicted to reduce peripheral neuropathy while maintaining systemic exposure, suggesting that personalizing paclitaxel dosing based on body composition may improve treatment outcomes.

Predicting outcomes of abdominal surgical emergencies in the elderly population using a CT muscle gauge.

BACKGROUND: Frailty has been shown to be an independent negative predictor of surgical outcomes in geriatric patients. Traditional measurements of muscle strength and mass are impractical in emergency settings, and computed tomography (CT)-measured skeletal muscle mass has been proposed as an alternative. However, the cutoff values for low muscle mass are still unknown, and their impact on abdominal emergencies in the elderly population is unclear. METHODS: A total of 462 young trauma patients aged 18-40 years were analyzed to establish sex-specific reference cutoff values for the CT-measured muscle index (MI) and muscle gauge (MG) values. The impacts of low MI and MG values were investigated in 1192 elderly patients (aged ≥ 65 years) undergoing abdominal surgery. RESULTS: The sex-specific cutoff values for MI and MG were determined by adopting European Working Group on Sarcopenia in Older People 2 guidelines. The correlation between MG and aging was significantly stronger than that between MI and ageing. With regard to the MG, the L4 psoas muscle gauge (L4 PMG) was further investigated in an elderly cohort owing to its high predictive value and ease of use in the clinical setting. A low L4 PMG value was an independent risk factor for overall complications and mortality in elderly patients with abdominal emergencies. CONCLUSION: The current study was the largest study investigating the correlations between MG values and aging in the Asian population. A low L4 PMG value may help surgeons during preoperative decision making regarding geriatric patients with abdominal emergencies.

Automated Measurements of Muscle Mass Using Deep Learning Can Predict Clinical Outcomes in Patients With Liver Disease.

INTRODUCTION: There is increasing recognition of the central role of muscle mass in predicting clinical outcomes in patients with liver disease. Muscle size can be extracted from computed tomography (CT) scans, but clinical implementation will require increased automation. We hypothesize that we can achieve this by using artificial intelligence. METHODS: Using deep convolutional neural networks, we trained an algorithm on the Reference Analytic Morphomics Population (n = 5,268) and validated the automated methodology in an external cohort of adult kidney donors with a noncontrast CT scan (n = 1,655). To test the clinical usefulness, we examined its ability to predict clinical outcomes in a prospectively followed cohort of patients with clinically diagnosed cirrhosis (n = 254). RESULTS: Between the manual and automated methodologies, we found excellent inter-rater agreement with an intraclass correlation coefficient of 0.957 (confidence interval 0.953-0.961, P < 0.0001) in the adult kidney donor cohort. The calculated dice similarity coefficient was 0.932 ± 0.042, suggesting excellent spatial overlap between manual and automated methodologies. To assess the clinical usefulness, we examined its ability to predict clinical outcomes in a cirrhosis cohort and found that automated psoas muscle index was independently associated with mortality after adjusting for age, gender, and child's classification (P < 0.001). DISCUSSION: We demonstrated that deep learning techniques can allow for automation of muscle measurements on clinical CT scans in a diseased cohort. These automated psoas size measurements were predictive of mortality in patients with cirrhosis showing proof of principal that this methodology may allow for wider implementation in the clinical arena.

Short-wave infrared light imaging measures tissue moisture and distinguishes superficial from deep burns.

Existing clinical approaches and tools to measure burn tissue destruction are limited resulting in misdiagnosis of injury depth in over 40% of cases. Thus, our objective in this study was to characterize the ability of short-wave infrared (SWIR) imaging to detect moisture levels as a surrogate for tissue viability with resolution to differentiate between burns of various depths. To accomplish our aim, we constructed an imaging system consisting of a broad-band Tungsten light source; 1,200-, 1,650-, 1,940-, and 2,250-nm wavelength filters; and a specialized SWIR camera. We initially used agar slabs to provide a baseline spectrum for SWIR light imaging and demonstrated the differential absorbance at the multiple wavelengths, with 1,940 nm being the highest absorbed wavelength. These spectral bands were then demonstrated to detect levels of moisture in inorganic and in vivo mice models. The multiwavelength SWIR imaging approach was used to diagnose depth of burns using an in vivo porcine burn model. Healthy and injured skin regions were imaged 72 hours after short (20 seconds) and long (60 seconds) burn application, and biopsies were extracted from those regions for histologic analysis. Burn depth analysis based on collagen coagulation histology confirmed the formation of superficial and deep burns. SWIR multispectral reflectance imaging showed enhanced intensity levels in long burned regions, which correlated with histology and distinguished between superficial and deep burns. This SWIR imaging method represents a novel, real-time method to objectively distinguishing superficial from deep burns.

Morphomic Signatures Derived from Computed Tomography Predict Hepatocellular Carcinoma Occurrence in Cirrhotic Patients.

BACKGROUND AND AIMS: Computed tomography (CT) provides scans of the human body from which digitized features can be extracted. The aim of this study was to examine the role of these digital biomarkers for predicting subsequent occurrence of hepatocellular carcinoma (HCC) in cirrhotic patients. METHODS: A cohort of 269 patients with cirrhosis were recruited and prospectively followed for the occurrence of HCC in Taiwan. CT scans were retrospectively retrieved and computationally processed using analytic morphomics. A predictive score was constructed using Cox regression and the generalized iterative modeling method, maximizing the log likelihood of the time to HCC development. An independent cohort of 274 patients from University of Michigan was utilized to examine the predictive validity of this score in a Western population. RESULTS: Of the 27 digitized features at the 12th thoracic vertebral level, six features were significantly associated with HCC occurrence. Two digitized features (fascia eccentricity and the bone mineral density) were able to stratify patients into high- and low-risk groups with distinct cumulative incidence of HCC in both the training and validation cohorts (P = 0.015 and 0.044, respectively). When the two digitized features were tested in the Michigan cohort, only bone mineral density remained an effective predictor. CONCLUSION: Digitized features derived from the CT were effective in predicting subsequent occurrence of HCC in cirrhosis patients. The bone mineral density measured on CT was an effective predictor for patients in both Taiwan and USA.

CT validation of SVC-RA junction location for pediatric central line placement: is vertebral bodies below the carina accurate?

PURPOSE: The key landmark for tip position of a central venous catheter (CVC) is the SVC-RA junction. In adults, localization of the SVC-RA junction may be assessed as a function of vertebral body units (VBU) below the carina during CVC placement. We investigated the relationship between the SVC-RA junction and the carina in children. MATERIALS AND METHODS: 584 CT scans of 0-18 years were analyzed. The carina was marked automatically by software while the SVC-RA junction and vertebrae were marked manually. The SVC-RA junction to carina (JC) distance was the primary study measurement reported in both VBU and mm. RESULTS: The data show an average JC distance of 1.25 VBU for 0-1 year, 1.27 VBU for 1-4 years, 1.34 VBU for 4-9 years, 1.53 VBU for 9-15 years, and 1.64 VBU for 15-18 years. A positive relationship between weight and JC distance was also demonstrated. CONCLUSION: JC distance is a useful predictor of SVC-RA junction location in children. Significant relationships were shown between JC distance and both age and weight. Due to small differences between age groups, however, average JC distance for all comers (1.48 VBU, 95% CI 0.7 - 2.3) can be used for SVC-RA junction identification in CVC placement.

Regional maps of rib cortical bone thickness and cross-sectional geometry.

Here we present detailed regional bone thickness and cross-sectional measurements from full adult ribs using high resolution CT scans processed with a cortical bone mapping technique. Sixth ribs from 33 subjects ranging from 24 to 99 years of age were used to produce average cortical bone thickness maps and to provide average ± 1SD corridors for expected cross-section properties (cross-sectional areas and inertial moments) as a function of rib length. Results obtained from CT data were validated at specific rib locations using direct measurements from cut sections. Individual thickness measurements from CT had an accuracy (mean error) and precision (SD error) of -0.013 ± 0.167 mm (R2 coefficient of determination of 0.84). CT-based measurement errors for rib cross-sectional geometry were -0.1 ± 13.1% (cortical bone cross-sectional area) and 4.7 ± 1.8% (total cross-sectional area). Rib cortical bone thickness maps show the expected regional variation across a typical rib's surface. The local mid-rib maxima in cortical thickness along the pleural rib aspect ranged from range 0.9 to 2.6 mm across the study population with an average map maximum of 1.4 mm. Along the cutaneous aspect, rib cortical bone thickness ranged from 0.7 to 1.9 mm with an average map thickness of 0.9 mm. Average cross-sectional properties show a steady reduction in total cortical bone area from 10% along the rib's length through to the sternal end, whereas overall cross-sectional area remains relatively constant along the majority of the rib's length before rising steeply towards the sternal end. On average, male ribs contained more cortical bone within a given cross-section than was seen for female ribs. Importantly, however, this difference was driven by male ribs having larger overall cross-sectional areas, rather than by sex differences in the bone thickness observed at specific local cortex sites. The cortical bone thickness results here can be used directly to improve the accuracy of current human body and rib models. Furthermore, the measurement corridors obtained from adult subjects across a wide age range can be used to validate future measurements from more widely available image sources such as clinical CT where gold standard reference measures (e.g. such as direct measurements obtained from cut sections) are otherwise unobtainable.

Computed Tomography Evidence of Psoas Muscle Atrophy Without Concomitant Tendon Wasting in Early Sepsis.

BACKGROUND: Morphomic studies have demonstrated a correlation between sarcopenia and clinical outcomes in septic patients. However, tendon morphomics has not yet been studied in this context. The purpose of the present study was to evaluate tendon morphology in septic patients through analytic morphomics. We hypothesized that morphomic analyses would reveal concomitant muscle and tendon wasting in sepsis patients. The results of this study may help to implement different rehabilitation modalities for critically ill patients. MATERIALS AND METHODS: The volume and fat content of bilateral psoas muscles and tendons were measured on abdominal computed tomography scans of 25 ICU septic and 25 control trauma patients admitted to the University of Michigan between 2011 and 2012. Univariate and multivariate analyses were performed to determine the relationship between psoas muscle and tendon morphometric data, and the association with clinical variables such as smoking and comorbidities. RESULTS: Average psoas muscle volume was 12.21 ± 5.6 cm3 for control patients and 9.318 ± 3.3 cm3 in septic patients (P = 0.0023). The average psoas muscle/fat ratio for septic patients was 0.0288 ± 0.071 cm3, compared with 0.0107 ± 0.008 cm3 in the control group (P = 0.075). Average tendon volume in the septic population (0.508 ± 0.191 cm3) was not different than the control cohort (0.493 ± 0.182 cm3) (P = 0.692). CONCLUSIONS: Our results demonstrate significantly smaller psoas muscle volume in septic patients than in age-, gender-, and BMI-matched trauma patients but no demonstrable change in tendon morphology between patient groups. These findings begin to define the boundaries of clinical application within the field of morphomics.

Measurement of Skeletal Muscle Area Improves Estimation of Aminoglycoside Clearance across Body Size.

A consistent approach to the dosing of aminoglycosides across the modern body size distribution has been elusive. We evaluated whether radiologically derived measures of body composition could explain more of the interpatient variability in aminoglycoside pharmacokinetics (PK) than standard body size metrics. This retrospective study included adult patients treated with gentamicin or tobramycin with at least three drug concentrations and computed tomography (CT) imaging available. Aminoglycoside volume and clearance (CL) estimates were computed using a two-compartment model by Bayesian analysis. Morphomic data were extracted from CT images using a custom algorithm. Bivariable and multivariable linear regression were used to assess relationships between PK parameters and covariates. A total of 335 patients were included with a median (minimum, maximum) of 4 (3, 16) aminoglycoside concentrations per patient. The median (minimum, maximum) age, height, and weight of included patients were 57 (21, 93) years, 170 (145, 203) centimeters, and 81 (42, 187) kilograms. Both standard and morphomic measures poorly explained variability in volume (R2 < 0.06). Skeletal muscle area and volume explained more of the interpatient variability in CL than weight or sex. Higher precision was observed using a modified Cockcroft-Gault equation with skeletal muscle area at L3 (R2= 0.38) or L4 (R2= 0.37) than the standard Cockcroft-Gault equation using lean (R2= 0.23), adjusted (R2= 0.23), or total (R2= 0.22) body weights. These results highlight that skeletal muscle measurements from CT images obtained in the course of care can improve the precision of aminoglycoside CL estimation over current body size scalars.

Relationships of Vancomycin Pharmacokinetics to Body Size and Composition Using a Novel Pharmacomorphomic Approach Based on Medical Imaging.

Antibiotics such as vancomycin are empirically dosed on the basis of body weight, which may not be optimal across the expanding adult body size distribution. Our aim was to compare the relationships between morphomic parameters generated from computed tomography images to conventional body size metrics as predictors of vancomycin pharmacokinetics (PK). This single-center retrospective study included 300 patients with 1,622 vancomycin concentration (52% trough) measurements. Bayesian estimation was used to compute individual vancomycin volume of distribution of the central compartment (Vc) and clearance (CL). Approximately 45% of patients were obese with an overall median (5th, 95th percentile) weight and body mass index of 87.2 (54.7, 123) kg and 28.8 (18.9, 43.7) kg/m2, respectively. Morphomic parameters of body size such as body depth, total body area, and torso volume of the twelfth thoracic through fourth lumbar vertebrae (T12 to L4) correlated with Vc. The relationship of vancomycin Vc was poorly predicted by body size but was stronger with T12-to-L4 torso volume (coefficient of determination [R2] = 0.11) than weight (R2 = 0.04). No relationships between vancomycin CL and traditional body size metrics could be discerned; however, relationships with skeletal muscle volume and total psoas area were found. Vancomycin CL independently correlated with total psoas area and inversely correlated with age. Thus, vancomycin CL was significantly related to total psoas area over age (R2 = 0.23, P < 0.0001). This proof-of-concept study suggests a potential role for translation of radiographic information into parameters predictive of drug pharmacokinetics. Prediction of individual antimicrobial pharmacokinetic parameters using analytic morphomics has the potential to improve antimicrobial dose selection and outcomes of obese patients.

The effect of age and demographics on rib shape.

Elderly populations have a higher risk of rib fractures and other associated thoracic injuries than younger adults, and the changes in body morphology that occur with age are a potential cause of this increased risk. Rib centroidal path geometry for 20 627 ribs was extracted from computed tomography (CT) scans of 1042 live adult subjects, then fitted to a six-parameter mathematical model that accurately characterizes rib size and shape, and a three-parameter model of rib orientation within the body. Multivariable regression characterized the independent effect of age, height, weight, and sex on the rib shape and orientation across the adult population, and statistically significant effects were seen from all demographic factors (P < 0.0001). This study reports a novel aging effect whereby both the rib end-to-end separation and rib aspect ratio are seen to increase with age, producing elongated and flatter overall rib shapes in elderly populations, with age alone explaining up to 20% of population variability in the aspect ratio of mid-level ribs. Age was not strongly associated with overall rib arc length, indicating that age effects were related to shape change rather than overall bone length. The rib shape effect was found to be more strongly and directly associated with age than previously documented age-related changes in rib angulation. Other demographic results showed height and sex being most strongly associated with rib size, and weight most strongly associated with rib pump-handle angle. Results from the study provide a statistical model for building rib shapes typical of any given demographic by age, height, weight, and sex, and can be used to help build population-specific computational models of the thoracic rib cage. Furthermore, results also quantify normal population ranges for rib shape parameters which can be used to improve the assessment and treatment of rib skeletal deformity and disease.

Morphometric age and survival following kidney transplantation.

BACKGROUND: As patients with chronic kidney disease become older, there is greater need to identify who will most benefit from kidney transplantation. Analytic morphomics has emerged as an objective risk assessment tool distinct from chronologic age. We hypothesize that morphometric age is a significant predictor of survival following transplantation. METHODS: A retrospective cohort of 158 kidney transplant patients from 2005 to 2014 with 1-year preoperative imaging was identified. Based on a control population comprising of trauma patients and kidney donors, morphometric age was calculated using the validated characteristics of psoas area, psoas density, and abdominal aortic calcification. The primary outcome was post-transplant survival. RESULTS: Cox regression showed morphometric age was a significant predictor of survival (hazard ratio, 1.06 per morphometric year [95% confidence interval, 1.03-1.08]; P < .001). Chronological age was not significant (hazard ratio, 1.03 per year [0.98-1.07]; P = .22). Among the chronologically oldest patients, those with younger morphometric age had greater survival rates compared to those with older morphometric age. CONCLUSIONS: Morphometric age predicts survival following kidney transplantation. Particularly for older patients, it offers improved risk stratification compared to chronologic age. Morphomics may improve the transplant selection process and provide a greater assessment of prospective survival benefits.

Using analytic morphomics to describe body composition associated with post-kidney transplantation diabetes mellitus.

BACKGROUND: Better risk assessment tools are needed to predict post-transplantation diabetes mellitus (PTDM). Using analytic morphomic measurements from computed tomography (CT) scans, we aimed to identify specific measures of body composition associated with PTDM. METHODS: We retrospectively reviewed 99 non-diabetic kidney transplant recipients who received pre-transplant CT scans at a single institution between 1/2005 and 5/2014. Analytic morphomic techniques were used to measure abdominal adiposity, abdominal size, and psoas muscle area and density, standardized by gender. We measured the associations of these morphomic factors with PTDM. RESULTS: One-year incidence of PTDM was 18%. The morphomic factors significantly associated with PTDM included visceral fat area (OR=1.84 per standard deviation increase, P=.020), body depth (OR=1.79, P=.035), and total body area (OR=1.67, P=.049). Clinical factors significantly associated with PTDM included African American race (OR=3.01, P=.044), hypertension (OR=2.97, P=.041), and dialysis vintage (OR=1.24 per year on dialysis, P=.048). Body mass index was not associated with PTDM (OR=1.05, P=.188). On multivariate modeling, visceral fat area was an independent predictor of PTDM (OR=1.91, P=.035). CONCLUSIONS: Analytic morphomics can identify pre-transplant measurements of body composition that are predictive of PTDM in kidney transplant recipients. Pre-transplant imaging contains a wealth of underutilized data that may inform PTDM prevention strategies.

Lymphatic Contribution to the Cellular Niche in Heterotopic Ossification.

OBJECTIVE: The objective of this study was to determine the contribution of lymphatic tissue to heterotopic ossification (HO). BACKGROUND: HO is the pathologic development of ectopic bone within soft tissues often following severe trauma. Characterization of the tissue niche supporting HO is critical to identifying therapies directed against this condition. Lymphangiogenesis is upregulated during incidents of trauma, thereby coincident with the niche supportive of HO. We hypothesized that lymphatic tissues play a critical role in HO formation. METHODS: Mice underwent hindlimb Achilles' tendon transection and dorsal burn injury (burn/tenotomy) to induce HO. The popliteal and inguinal lymph nodes were excised ipsilateral to the tenotomy site. Flow cytometry and immunostaining were used to quantify and localize lymphoendothelium. MicroCT was used to quantify HO. RESULTS: Enrichment of mature lymphatic tissues was noted 2 weeks after injury at the tendon transection sites when compared with the contralateral, intact tendon based on LYVE1+ tubules (10.9% vs 0.8%, P < 0.05). Excision of the inguinal and popliteal nodes with draining popliteal lymphatic vessel significantly decreased the presence of mature lymphoendothelium 2 weeks after injury (10.9% vs 3.3%, P < 0.05). Bone-cartilage-stromal progenitor cells (CD105+/AlphaV+/Tie2-/CD45-/CD90-/BP1-) were also significantly decreased after lymph node excision (10.2% vs 0.5%, P < 0.05). A significant decrease was noted in the volume of de novo HO present within the soft tissues (0.12 mm vs 0.02 mm). CONCLUSION: These findings suggest that lymphatic vessels are intimately linked with the de novo formation bone within soft tissues following trauma, and their presence may facilitate bone formation.

Bone mineral density predicts posttransplant survival among hepatocellular carcinoma liver transplant recipients.

Hepatocellular carcinoma (HCC) is a common indication for liver transplantation (LT). Recent data suggest that body composition features strongly affect post-LT mortality. We examined the impact of body composition on post-LT mortality in patients with HCC. Data on adult LT recipients who received Model for End-Stage Liver Disease exception for HCC between February 29, 2002, and December 31, 2013, and who had a computed tomography (CT) scan any time 6 months prior to LT were reviewed (n = 118). All available CT scan Digital Imaging and Communication in Medicine files were analyzed using a semiautomated high throughput methodology with algorithms programmed in MATLAB. Analytic morphomics measurements including dorsal muscle group (DMG) area, visceral and subcutaneous fat, and bone mineral density (BMD) were taken at the bottom of the eleventh thoracic vertebral level. Thirty-two (27%) patients died during the median follow-up of 4.4 years. The number of HCC lesions (hazard ratio [HR], 2.81; P < 0.001), BMD (HR = 0.90/Hounsfield units [HU]; P = 0.03), pre-LT locoregional therapy (HR = 0.14; P < 0.001), and donor age (HR = 1.05; P < 0.001) were the independent predictors of post-LT mortality. DMG area did not affect post-LT survival. In conclusion, in addition to number of HCC lesions and pre-LT locoregional therapy, low BMD, a surrogate for bone loss rather than DMG area, was independently associated with post-LT mortality in HCC patients. Bone loss may be an early marker of deconditioning that precedes sarcopenia and may affect transplant outcomes. Liver Transplantation 22 1092-1098 2016 AASLD.

The role of the adaptive immune system in burn-induced heterotopic ossification and mesenchymal cell osteogenic differentiation.

BACKGROUND: Heterotopic ossification (HO) is the pathologic process of extraskeletal bone formation. Although the exact etiology remains unknown, inflammation appears to catalyze disease progression. The goal of this study is to determine the impact of the adaptive immune system on HO. METHODS: HO was induced in 8-wk-old control C57BL/6 and immunocompromised Rag1tm1Mom (Rag1 KO) male mice deficient in B- and T-lymphocytes via combined Achilles tenotomy and burn injury. Microcomputed tomography quantified the extent of HO formation at the tenotomy site. Adipose-derived mesenchymal stem cells were harvested to evaluate osteogenic differentiation potential. RESULTS: Areas of developing HO demonstrated substantial enrichment of CD45 + leukocytes at 3 wk after injury. HO from Rag1 KO mice was substantially less mature with foci of cartilage and disorganized trabecular bone present 12 wk after injury. Rag1 KO mice formed 60% less bone compared to immunocompetent controls (4.67 ± 1.5 mm versus 7.76 ± 0.65 mm; P = 0.001). Tartrate-resistant acid phosphatase staining and immunofluorescent analysis of osteoprotegerin and nuclear factor kappa-light-chain-enhancer of activated B cells demonstrated no appreciable difference in osteoclast number or activation. Alizarin red staining in vitro demonstrated a significant decrease in osteogenic potential in immunocompromised mice compared to controls (29.1 ± 0.54 mm versus 12.1 ± 0.14 mm; P < 0.001). CONCLUSIONS: We demonstrate a prominent role for the adaptive immune system in the development of HO. In the absence of mature B- and T-lymphocytes, HO growth and development are attenuated. Furthermore, we demonstrate that mesenchymal populations from B- and T-cell deficient mice are inherently less osteogenic. This study identifies a potential therapeutic role for modulation of the adaptive immune system in the treatment of HO.

Abdominal adiposity, body composition and survival after liver transplantation.

BACKGROUND: Current measures of obesity do not accurately describe body composition. Using cross-sectional imaging, objective measures of musculature and adiposity are possible and may inform efforts to optimize liver transplantation outcomes. METHODS: Abdominal visceral fat area and psoas muscle cross-sectional area were measured on CT scans for 348 liver transplant recipients. After controlling for donor and recipient characteristics, survival analysis was performed using Cox regression. RESULTS: Visceral fat area was significantly associated with post-transplant mortality (p < 0.001; HR = 1.06 per 10 cm(2) , 95% CI: 1.04-1.09), as were positive hepatitis C status (p = 0.004; HR = 1.78, 95% CI: 1.21-2.61) and total psoas area (TPA) (p < 0.001; HR = 0.91 per cm(2) , 95% CI: 0.88-0.94). Among patients with smaller TPA, the patients with high visceral fat area had 71.8% one-yr survival compared to 81.8% for those with low visceral fat area (p = 0.15). At five yr, the smaller muscle patients with high visceral fat area had 36.9% survival compared to 58.2% for those with low visceral fat area (p = 0.023). CONCLUSIONS: Abdominal adiposity is associated with survival after liver transplantation, especially in patients with small trunk muscle size. When coupled with trunk musculature, abdominal adiposity offers direct characterization of body composition that can aid preoperative risk evaluation and inform transplant decision-making.