Skeletal muscle gauge prediction by a machine learning model in patients with colorectal cancer.

OBJECTIVES: Skeletal muscle gauge (SMG) was recently introduced as an imaging indicator of sarcopenia. Computed tomography is essential for measuring SMG; thus, the use of SMG is limited to patients who undergo computed tomography. We aimed to develop a machine learning algorithm using clinical and inflammatory markers to predict SMG in patients with colorectal cancer. METHODS: The least absolute shrinkage and selection operator regression model was applied for variable selection and predictive signature building in the training set. The predictive accuracy of the least absolute shrinkage and selection operator model, defined as linear predictor (LP)-SMG, was compared using the area under the receiver operating characteristic curve and decision curve analysis in the test set. RESULTS: A total of 1094 patients with colorectal cancer were enrolled and randomly categorized into training (n = 656) and test (n = 438) sets. Low SMG was identified in 142 (21.6%) and 90 (20.5%) patients in the training and test sets, respectively. According to multivariable analysis of the test sets, LP-SMG was identified as an independent predictor of low SMG (odds ratio = 1329.431; 95% CI, 271.684-7667.996; P < .001). Its predictive performance was similar in the training and test sets (area under the receiver operating characteristic curve = 0.846 versus 0.869; P = .427). In the test set, LP-SMG had better outcomes in predicting SMG than single clinical variables, such as sex, height, weight, and hemoglobin. CONCLUSIONS: LP-SMG had superior performance than single variables in predicting low SMG. This machine learning model can be used as a screening tool to detect sarcopenic status without using computed tomography during the treatment period.

Novel extended IVIVC combined with DoE to predict pharmacokinetics from formulation compositions.

The objective of this study was to develop a novel extended in vitro in vivo correlation (IVIVC) model combined with design of experiment (DoE) that integrates the DoE into IVIVC, which can predict the pharmacokinetics of sustained-release (SR) tablets from their formulation compositions, and vice versa. To develop the extended IVIVC model, ketoprofen was used as a model drug. Nineteen types of ketoprofen SR tablets with different formulation compositions were prepared based on the mixture design and used to derive mathematical relationships between the formulation composition and the in vitro dissolution profiles for DoE. The predictability of the DoE equation was externally validated by using additional seven types of SR formulations with prediction errors (%PE) of less than 11.45%. For the development of IVIVC model, three SR formulations that have fast, medium, and slow drug-releasing rates were selected, and the in vivo pharmacokinetics were assessed in Beagle dogs. The pharmacokinetic properties of ketoprofen SR tablets were described by a population pharmacokinetics (POP-PK) model which incorporated the pH-dependent dissolution of ketoprofen by a time-dependent Hill-type equation. The final POP-PK model could describe the overall in vivo pharmacokinetic profiles and allowed estimation of the in vivo dissolution parameters. The POP-PK model estimated in vivo dissolution parameter, Kdiss, in vivo were then correlated with the in vitro dissolution parameter, Kdiss, in vitro by linear regression (R2 = 0.9989), establishing IVIVC. Finally, the equation derived from DoE was introduced to the IVIVC model to develop the extended IVIVC, which connects the formulation composition, in vitro dissolution, and in vivo pharmacokinetic profiles. The average %PE of the final extended IVIVC model was 4.24% for Cmax and 4.46% and AUC. Finally, the final extended IVIVC was applied to predict the in vivo PK profiles of SR tablets from their formulation compositions as well as to design the optimal formulation to achieve certain target PK profiles. The %PE of the final extended IVIVC model was less than 14.67% for Cmax and 12.41% for AUC, satisfying the FDA criteria of conventional IVIVC. The present extended IVIVC model may provide a useful tool towards rationalized design and development of new SR formulations.

A Clinical Trial to Evaluate the Efficacy and Safety of 3D Printed Bioceramic Implants for the Reconstruction of Zygomatic Bone Defects.

The purpose of this study was to evaluate the clinical efficacy and safety of patient-specific additive-manufactured CaOSiO2-P2O5-B2O3 glass-ceramic (BGS-7) implants for reconstructing zygomatic bone defects at a 6-month follow-up. A prospective, single-arm, single-center, clinical trial was performed on patients with obvious zygoma defects who needed and wanted reconstruction. The primary outcome variable was a bone fusion between the implant and the bone evaluated by computed tomography (CT) at 6 months post surgery. Secondary outcomes, including implant immobilization, satisfaction assessment, osteolysis, subsidence of the BGS-7 implant, and safety, were assessed. A total of eight patients were enrolled in the study. Two patients underwent simultaneous reconstruction of the left and right malar defects using a BGS-7 3D printed implant. Cone beam CT analysis showed that bone fusion at 6 months after surgery was 100%. We observed that the average fusion rate was 76.97%. Osteolysis around 3D printed BGS-7 implants was not observed. The mean distance displacement of all 10 implants was 0.4149 mm. Our study showed no adverse event in any of the cases. The visual analog scale score for satisfaction was 9. All patients who enrolled in this trial were aesthetically and functionally satisfied with the surgical results. In conclusion, this study demonstrates the safety and promising value of patient-specific 3D printed BGS-7 implants as a novel facial bone reconstruction method.

Simultaneous analysis of acetylcarnitine, proline, hydroxyproline, citrulline, and arginine as potential plasma biomarkers to evaluate NSAIDs-induced gastric injury by liquid chromatography-tandem mass spectrometry.

Although major adverse effects associated with nonsteroidal anti-inflammatory drugs (NSAIDs) are gastric injury, assessment of NSAIDs-induced gastrointestinal adverse effects is mostly dependent on endoscopy due to the lack of plasma biomarkers. Several amino acids associated with collagenase activity and gastric mucosal mass have been suggested as plasma biomarker candidates for gastric injury. Therefore, this study aimed to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the plasma biomarker candidates, i.e., acetylcarnitine, proline, hydroxyproline, citrulline, and arginine and evaluate their potential as a biomarker for NSAIDs-induced gastric injury. The method utilized simple protein precipitation with methanol and D4-citrulline as an internal standard (IS). The assay resulted in the lower limit of quantification (LLOQ) of 0.1 µg/mL for acetylcarnitine and 1 µg/mL for proline, hydroxyproline, citrulline, and arginine in the surrogate blank plasma. The intra- and inter-day accuracy ranged 82.5-111.2% for acetylcarnitine, 95.4-103.3% for proline, 98.9-106.4% for hydroxyproline, 99.5-103.5% for citrulline, and 87.4-105.3% for arginine. The precision was within 6.17%, 3.63%, 6.20%, 6.31%, and 6.17% for acetylcarnitine, proline, hydroxyproline, citrulline, and arginine, respectively. The developed assay was successfully applied to monitor the changes of the plasma levels of the five amino acids in rats and Beagle dogs following repeated oral administrations of aceclofenac. In rats, plasma concentrations of proline, hydroxyproline, and citrulline were significantly reduced after 4 days of aceclofenac administration compared to the control group. In dogs, plasma concentrations of proline and citrulline were significantly decreased after 7 days of aceclofenac administration compared to those obtained after the first aceclofenac administration. These data indicate that plasma levels of proline, hydroxyproline, and citrulline may be used as quantitative biomarkers of NSAIDs-induced gastric damage. The present assay could also be utilized to monitor the changes of these amino acids as potential indicators for various physiological and pathophysiological conditions.

Regional Absorption of Fimasartan in the Gastrointestinal Tract by an Improved in situ Absorption Method in Rats.

The aim of the present study was to assess the regional absorption of fimasartan by an improved in situ absorption method in comparison with the conventional in situ single-pass perfusion method in rats. After each gastrointestinal segment of interest was identified, fimasartan was injected into the starting point of each segment and the unabsorbed fimasartan was discharged from the end point of the segment. Blood samples were collected from the jugular vein to evaluate the systemic absorption of the drug. The relative fraction absorbed (Fabs,relative) values in the specific gastrointestinal region calculated based on the area under the curve (AUC) values obtained after the injection of fimasartan into the gastrointestinal segment were 8.2% ± 3.2%, 23.0% ± 12.1%, 49.7% ± 11.5%, and 19.1% ± 11.9% for the stomach, duodenum, small intestine, and large intestine, respectively, which were comparable with those determined by the conventional in situ single-pass perfusion. By applying the fraction of the dose available at each gastrointestinal segment following the oral administration, the actual fraction absorbed (F'abs) values at each gastrointestinal segment were estimated at 10.9% for the stomach, 27.1% for the duodenum, 40.7% for the small intestine, and 5.4% for the large intestine, which added up to the gastrointestinal bioavailability (FX·FG) of 84.1%. The present method holds great promise to assess the regional absorption of a drug and aid to design new drug formulations.

Pharmacokinetics and Anti-Gastric Ulceration Activity of Oral Administration of Aceclofenac and Esomeprazole in Rats.

This study examined the effects of esomeprazole on aceclofenac pharmacokinetics and gastrointestinal complications in rats. Aceclofenac alone, or in combination with esomeprazole, was orally administered to male Sprague-Dawley rats. Plasma concentrations of aceclofenac, its major metabolite diclofenac, and esomeprazole were simultaneously determined by a novel liquid chromatography-tandem mass spectrometry method. Gastrointestinal damage was determined by measuring ulcer area and ulcer lesion index of the stomach. Oral administration of aceclofenac induced significant gastric ulceration, which was inhibited by esomeprazole administration. Following concurrent administration of aceclofenac and esomeprazole, overall pharmacokinetic profiles of aceclofenac and metabolic conversion to diclofenac were unaffected by esomeprazole. Aceclofenac metabolism and pharmacokinetics were not subject to significant food effects, whereas bioavailability of esomeprazole decreased in fed compared to fasting conditions. In contrast, the pharmacokinetics of aceclofenac and esomeprazole were significantly altered by different dosing vehicles. These results suggest that co-administration of esomeprazole with aceclofenac may reduce aceclofenac-induced gastrointestinal complications without significant pharmacokinetic interactions. The optimal combination and clinical significance of the benefits of the combination of aceclofenac and esomeprazole need to be further evaluated.

Exploring for the optimal structural design for the 3D-printing technology for cranial reconstruction: a biomechanical and histological study comparison of solid vs. porous structure.

PURPOSE: Cranioplasty for recovering skull defects carries the risk for a number of complications. Various materials are used, including autologous bone graft, metallic materials, and non-metallic materials, each of which has advantages and disadvantages. If the use of autologous bone is not feasible, those artificial materials also have constraints in the case of complex anatomy and/or irregular defects. MATERIAL AND METHODS: This study used metal 3D-printing technology to overcome these existing drawbacks and analyze the clinical and mechanical performance requirements. To find an optimal structure that satisfied the structural and mechanical stability requirements, we evaluated biomechanical stability using finite element analysis (FEA) and mechanical testing. To ensure clinical applicability, the model was subjected to histological evaluation. Each specimen was implanted in the femur of a rabbit and was evaluated using histological measurements and push-out test. RESULTS AND CONCLUSION: We believe that our data will provide the basis for future applications of a variety of unit structures and further clinical trials and research, as well as the direction for the study of other patient-specific implants.

Sacral Reconstruction with a 3D-Printed Implant after Hemisacrectomy in a Patient with Sacral Osteosarcoma: 1-Year Follow-Up Result.

Pelvic reconstruction after sacral resection is challenging in terms of anatomical complexity, excessive loadbearing, and wide defects. Nevertheless, the technological development of 3D-printed implants enables us to overcome these difficulties. Here, we present a case of sacral osteosarcoma surgically treated with hemisacrectomy and sacral reconstruction using a 3D-printed implant. The implant was printed as a customized titanium prosthesis from a 3D real-sized reconstruction of a patient's CT images. It consisted mostly of a porous mesh and incorporated a dense strut. After 3-months of neoadjuvant chemotherapy, the patient underwent hemisacretomy with preservation of contralateral sacral nerves. The implant was anatomically installed on the defect and fixed with a screw-rod system up to the level of L3. Postoperative pain was significantly low and the patient recovered sufficiently to walk as early as 2 weeks postoperatively. The patient showed left-side foot drop only, without loss of sphincter function. In 1-year follow-up CT, excellent bony fusion was noticed. To our knowledge, this is the first report of a case of hemisacral reconstruction using a custom-made 3D-printed implant. We believe that this technique can be applied to spinal reconstructions after a partial or complete spondylectomy in a wide variety of spinal diseases.

Cranioplasty Enhanced by Three-Dimensional Printing: Custom-Made Three-Dimensional-Printed Titanium Implants for Skull Defects.

The authors studied to demonstrate the efficacy of custom-made three-dimensional (3D)-printed titanium implants for reconstructing skull defects. From 2013 to 2015, 21 patients (8-62 years old, mean = 28.6-year old; 11 females and 10 males) with skull defects were treated. Total disease duration ranged from 6 to 168 months (mean = 33.6 months). The size of skull defects ranged from 84 × 104 to 154 × 193 mm. Custom-made implants were manufactured by Medyssey Co, Ltd (Jecheon, South Korea) using 3D computed tomography data, Mimics software, and an electron beam melting machine. The team reviewed several different designs and simulated surgery using a 3D skull model. During the operation, the implant was fit to the defect without dead space. Operation times ranged from 85 to 180 minutes (mean = 115.7 minutes). Operative sites healed without any complications except for 1 patient who had red swelling with exudation at the skin defect, which was a skin infection and defect at the center of the scalp flap reoccurring since the initial head injury. This patient underwent reoperation for skin defect revision and replacement of the implant. Twenty-one patients were followed for 6 to 24 months (mean = 14.1 months). The patients were satisfied and had no recurrent wound problems. Head computed tomography after operation showed good fixation of titanium implants and satisfactory skull-shape symmetry. For the reconstruction of skull defects, the use of autologous bone grafts has been the treatment of choice. However, bone use depends on availability, defect size, and donor morbidity. As 3D printing techniques are further advanced, it is becoming possible to manufacture custom-made 3D titanium implants for skull reconstruction.