Breath Measurement Method for Synchronized Reproduction of Biological Tones in an Augmented Reality Auscultation Training System.

An educational augmented reality auscultation system (EARS) is proposed to enhance the reality of auscultation training using a simulated patient. The conventional EARS cannot accurately reproduce breath sounds according to the breathing of a simulated patient because the system instructs the breathing rhythm. In this study, we propose breath measurement methods that can be integrated into the chest piece of a stethoscope. We investigate methods using the thoracic variations and frequency characteristics of breath sounds. An accelerometer, a magnetic sensor, a gyro sensor, a pressure sensor, and a microphone were selected as the sensors. For measurement with the magnetic sensor, we proposed a method by detecting the breathing waveform in terms of changes in the magnetic field accompanying the surface deformation of the stethoscope based on thoracic variations using a magnet. During breath sound measurement, the frequency spectra of the breath sounds acquired by the built-in microphone were calculated. The breathing waveforms were obtained from the difference in characteristics between the breath sounds during exhalation and inhalation. The result showed the average value of the correlation coefficient with the reference value reached 0.45, indicating the effectiveness of this method as a breath measurement method. And the evaluations suggest more accurate breathing waveforms can be obtained by selecting the measurement method according to breathing method and measurement point.

Clinical Evaluation Based on a New Approach to Improve the Accuracy of 4ß-Hydroxycholesterol Measurement as a Biomarker of CYP3A4 Activity.

This study examines 4ß-Hydroxycholesterol (4ß-HC), which is considered to be a potential marker for the CYP3A4 induction of new chemical entities (NCEs) in drug development. To ensure the use of 4ß-HC as a practical biomarker, it is necessary to accurately measure 4ß-HC and demonstrate that CYP3A4 induction can be appropriately assessed, even for weak inducers. In clinical trials of NCEs, plasma is often collected with various anticoagulants, in some cases, the plasma is acidified, then stored for an extended period. In this study, we examined the effects of these manipulations on the measurement of 4ß-HC, and based on the results, we optimized the plasma collection and storage protocols. We also found that a cholesterol oxidation product is formed when plasma is stored, and by monitoring the compound, we were able to identify when plasma was stored inappropriately. After evaluating the above, clinical drug-drug interaction (DDI) studies were conducted using two NCEs (novel retinoid-related orphan receptor γ antagonists). The weak CYP3A4 induction by the NCEs (which were determined based on a slight decline in the systemic exposure of a probe substrate (midazolam)), was detected by the significant increase in 4ß-HC levels (more specifically, 4ß-HC/total cholesterol ratios). Our new approach, based on monitoring a cholesterol oxidation product to identify plasma that is stored inappropriately, allowed for the accurate measurement of 4ß-HC, and thus, it enabled the evaluation of weak CYP3A4 inducers in clinical studies without using a probe substrate.

A cysteine trapping assay for risk assessment of reactive acyl CoA metabolites.

Some drugs with carboxylic acid moieties can potentially cause rare but severe hepatotoxicity. The reactive chemical species generated by drug metabolism are thought to be one reason for this event. Although the phase II conjugation metabolism of carboxylic acids generally renders a compound more polar and inactive, it is also responsible for the formation of reactive metabolites.This study aimed to provide a new approach towards the risk assessment of carboxylic acids in the aspect of reactive acyl CoA metabolites.Although acyl CoA metabolites have been concerned, it is difficult to detect them because of their instability. We investigated the trapping agents for acyl CoA metabolites. We found that cysteine is a good trapping agent and developed an assay method for the reactivity of acyl CoA metabolites. We evaluated 17 drugs with carboxylic acid moieties, all drugs concerned with hepatotoxicity displayed reactive potential. With consideration of the exposure of each parent drug, the correlation between drug labels and the calculated risk of carboxylic drugs was improved.These evaluations can be conducted without radiochemical reagents or the authentic standards of metabolites. We believe that the method will be beneficial for drug discovery.

Randomized phase II study of tegafur-uracil/leucovorin versus tegafur-uracil/leucovorin plus oxaliplatin after curative resection of high-risk stage II/III colorectal cancer (SOAC-1101 trial).

PURPOSE: This randomized phase II trial compared tegafur-uracil/leucovorin (UFT/LV) plus oxaliplatin (TEGAFOX) to UFT/LV as adjuvant chemotherapy for patients with high-risk stage II/III colorectal cancer. METHODS: From 2010 to April 2015, 159 patients who underwent curative resection were randomly assigned to receive TEGAFOX (85 mg/m2 oxaliplatin on days 1 and 15, 300 mg/m2/day UFT and 75 mg/day LV on days 1-28, every 35 days for five cycles) or UFT/LV. The primary study endpoint was disease-free survival. RESULTS: The 3-year disease-free survival rate was 84.2% in the TEGAFOX arm, versus 62.1% for UFT/LV. The stratified hazard ratio for disease-free survival for TEGAFOX compared to UFT/LV was 0.338 (P < 0.01). The incidence of any-grade adverse events was significantly higher in the TEGAFOX arm (96.1%) than in the UFT/LV arm (76.6%; P < 0.01). The rates of any-grade neutropenia, thrombocytopenia, aspartate aminotransferase/alanine aminotransferase elevation, and peripheral sensory neuropathy were higher in the TEGAFOX group, whereas the incidence of grade ≥ 3 adverse events did not differ between the groups. CONCLUSIONS: TEGAFOX is an additional adjuvant chemotherapy option for high-risk stage II/III colorectal cancer. TRIAL REGISTRATION: UMIN ID: 000007696, date of registration: April 10, 2012.

Predicting blood-to-plasma concentration ratios of drugs from chemical structures and volumes of distribution in humans.

Despite their importance in determining the dosing regimen of drugs in the clinic, only a few studies have investigated methods for predicting blood-to-plasma concentration ratios (Rb). This study established an Rb prediction model incorporating typical human pharmacokinetics (PK) parameters. Experimental Rb values were compiled for 289 compounds, offering reliable predictions by expanding the applicability domain. Notably, it is the largest list of Rb values reported so far. Subsequently, human PK parameters calculated from plasma drug concentrations, including the volume of distribution (Vd), clearance, mean residence time, and plasma protein binding rate, as well as 2702 kinds of molecular descriptors, were used to construct quantitative structure-PK relationship models for Rb. Among the evaluated PK parameters, logVd correlated best with Rb (correlation coefficient of 0.47). Thus, in addition to molecular descriptors selected by XGBoost, logVd was employed to construct the prediction models. Among the analyzed algorithms, artificial neural networks gave the best results. Following optimization using six molecular descriptors and logVd, the model exhibited a correlation coefficient of 0.64 and a root-mean-square error of 0.205, which were superior to those previously reported for other Rb prediction methods. Since Vd values and chemical structures are known for most medications, the Rb prediction model described herein is expected to be valuable in clinical settings.

Evaluation of the changes in exposure to thiol compounds in chronic kidney disease patients using the PBPK model.

Targeted covalent inhibitors designed to bind covalently to a specific molecular target have recently been a focus of drug development. Among these inhibitors, thiol compounds bind covalently to endogenous thiols in the body through a process involving disulfide bonds. We investigated the predictability of changes in the exposure to captopril, tiopronin, the active form of dalcetrapib and the active metabolite of prasugrel, R-138727, all of which have a sulfhydryl group, in moderate and severe chronic kidney disease (CKD) patients using a constructed PBPK model. The changes in the exposure to captopril, tiopronin and the active form of dalcetrapib under CKD conditions were well predicted. However, the change in exposure to R-138727, which is a secondary metabolite of prasugrel, was overpredicted. Although these thiol compounds covalently bind to endogenous thiols, our study concluded that changes in exposure to these compounds under CKD conditions can probably be predicted, except for compounds with a complicated mechanism whereby the thiol metabolite is generated.

Evaluation of covalent binding of flutamide and its risk assessment using 19F-NMR.

The formation of reactive metabolites (RMs) is a problem in drug development that sometimes results in severe hepatotoxicity. As detecting RMs themselves is difficult, a covalent binding assay using expensive radiolabelled tracers is usually performed for candidate selection. This study aimed to provide a practical approach toward the risk assessment of hepatotoxicity induced by covalent binding before candidate selection. We focused on flutamide because it contains a trifluoromethyl group that shows a strong singlet peak by 19F nuclear magnetic resonance (NMR) spectrometry. The covalent binding of flutamide was evaluated using quantitative NMR and its risk for hepatotoxicity was assessed by estimating the RM burden, an index that reflects the body burden associated with RM exposure by determining the extent of covalent binding, clinical dose and in vivo clearance. The extent of covalent binding and RM burden was 296 pmol/mg/h and 37.9 mg/day, respectively. Flutamide was categorised as high risk with an RM burden >10 mg/day consistent with its clinical hepatotoxicity. These results indicate that a combination of covalent binding assay using 19F-NMR and RM burden is useful for the risk assessment of RMs without using radiolabelled compounds.

The influence of multiple oral administration on the pharmacokinetics and distribution profile of dalcetrapib in rats.

We investigated the influence of multiple oral administration on the accumulation of dalcetrapib (JTT-705/RO4607381), a novel cholesteryl ester transfer protein inhibitor, in rats. It is well known that orally administered dalcetrapib is rapidly hydrolysed to its active form, which has a sulfhydryl group, in the body. The active form then binds covalently to endogenous thiols via mixed disulfide bonds. Following multiple once daily oral administration of 14C-dalcetrapib for seven days to rats, the concentration of radioactivity in the plasma and almost all tissues reached the steady state by day 4. At 24 h after the last dose, there was a relatively high concentration of radioactivity in the mesenteric lymph nodes, liver, adrenal glands and fat. After the last dose to rats, the radioactivity was almost completely recovered in the urine and faeces, indicating that dalcetrapib is not retained in the body, probably due to the reversibility of the disulfide bonds despite being covalent bonds.

Automatic detection of actionable radiology reports using bidirectional encoder representations from transformers.

BACKGROUND: It is essential for radiologists to communicate actionable findings to the referring clinicians reliably. Natural language processing (NLP) has been shown to help identify free-text radiology reports including actionable findings. However, the application of recent deep learning techniques to radiology reports, which can improve the detection performance, has not been thoroughly examined. Moreover, free-text that clinicians input in the ordering form (order information) has seldom been used to identify actionable reports. This study aims to evaluate the benefits of two new approaches: (1) bidirectional encoder representations from transformers (BERT), a recent deep learning architecture in NLP, and (2) using order information in addition to radiology reports. METHODS: We performed a binary classification to distinguish actionable reports (i.e., radiology reports tagged as actionable in actual radiological practice) from non-actionable ones (those without an actionable tag). 90,923 Japanese radiology reports in our hospital were used, of which 788 (0.87%) were actionable. We evaluated four methods, statistical machine learning with logistic regression (LR) and with gradient boosting decision tree (GBDT), and deep learning with a bidirectional long short-term memory (LSTM) model and a publicly available Japanese BERT model. Each method was used with two different inputs, radiology reports alone and pairs of order information and radiology reports. Thus, eight experiments were conducted to examine the performance. RESULTS: Without order information, BERT achieved the highest area under the precision-recall curve (AUPRC) of 0.5138, which showed a statistically significant improvement over LR, GBDT, and LSTM, and the highest area under the receiver operating characteristic curve (AUROC) of 0.9516. Simply coupling the order information with the radiology reports slightly increased the AUPRC of BERT but did not lead to a statistically significant improvement. This may be due to the complexity of clinical decisions made by radiologists. CONCLUSIONS: BERT was assumed to be useful to detect actionable reports. More sophisticated methods are required to use order information effectively.

Unsupervised Deep Anomaly Detection in Chest Radiographs.

The purposes of this study are to propose an unsupervised anomaly detection method based on a deep neural network (DNN) model, which requires only normal images for training, and to evaluate its performance with a large chest radiograph dataset. We used the auto-encoding generative adversarial network (α-GAN) framework, which is a combination of a GAN and a variational autoencoder, as a DNN model. A total of 29,684 frontal chest radiographs from the Radiological Society of North America Pneumonia Detection Challenge dataset were used for this study (16,880 male and 12,804 female patients; average age, 47.0 years). All these images were labeled as "Normal," "No Opacity/Not Normal," or "Opacity" by board-certified radiologists. About 70% (6,853/9,790) of the Normal images were randomly sampled as the training dataset, and the rest were randomly split into the validation and test datasets in a ratio of 1:2 (7,610 and 15,221). Our anomaly detection system could correctly visualize various lesions including a lung mass, cardiomegaly, pleural effusion, bilateral hilar lymphadenopathy, and even dextrocardia. Our system detected the abnormal images with an area under the receiver operating characteristic curve (AUROC) of 0.752. The AUROCs for the abnormal labels Opacity and No Opacity/Not Normal were 0.838 and 0.704, respectively. Our DNN-based unsupervised anomaly detection method could successfully detect various diseases or anomalies in chest radiographs by training with only the normal images.

A Multicenter Phase 2 Trial to Evaluate the Efficacy of mFOLFOX6 + Cetuximab as Induction Chemotherapy to Achieve R0 Surgical Resection for Advanced Colorectal Liver Metastases (NEXTO Trial).

BACKGROUND: The effect of cetuximab plus mFOLFOX on downsizing of the tumors for curative resection has yet to be assessed for patients with advanced colorectal liver metastases (CRLMs). This study aimed to assess the oncologic benefit of cetuximab plus mFOLFOX for wild-type KRAS patients with advanced CRLMs. METHODS: In this multicenter phase 2 trial, patients with technically unresectable tumor and/or five or more CRLMs harboring wild-type KRAS were treated with mFOLFOX plus cetuximab. The patients were assessed for resectability after 4 treatments, and then every 2 months up to 12 treatments. Patients with resectable disease were offered surgery after a waiting period of 1 month. The primary end point of the study was the R0 resection rate. The secondary end points were safety, progression-free survival (PFS), and overall survival (OS). The study is registered with the University Hospital Medical Information Network-Clinical Trials Registry Clinical Trials Registry (no. C000007923). RESULTS: Between 2012 and 2015, 50 patients from 13 centers were enrolled in this trial. Two patients were excluded because they had not received induction therapy. The 48 patients had a complete response rate of 0% and a partial response rate of 64.6%. For 26 R0 resections (54.2%) and 5 R1 resections (10.4%), no mortality occurred. During a median follow-up period of 31 months, the median OS for all the patients was calculated to be 41 months (95% confidence interval, 28-not reached). The 3-year OS rate was 59%. CONCLUSION: For patients with advanced CRLMs harboring wild-type KRAS, cetuximab administered in combination with mFOLFOX yields high response rates, leading to significantly high R0 resection rates and favorable prognoses.

Bundle interventions including nontechnical skills for surgeons can reduce operative time and improve patient safety.

OBJECTIVE: This study aimed to determine if introducing nontechnical skills to surgical trainees during surgical education can reduce the operation time and contribute to patient safety. DESIGN: Quality improvement initiatives using the KAIZEN as a problem-solving method. SETTING: Department of surgery in a referral and educational hospital. PARTICIPANTS: Surgical team and quality management team. INTERVENTION: The KAIZEN was used as a problem-solving method between 2015 and 2018 to reduce the operation time. First, baseline measurement was performed to understand the current situations in our department. To achieve continuous improvement, periodical feedback of the current status was obtained from all staff. Bundles, including nontechnical skills, were established. Briefing and debriefing were performed by the surgical team. MAIN OUTCOME MEASURES: Excessively long operation rates with a standard procedure. RESULTS: We included 1573 operations in this initiative. Excessively long operation rates were reduced in all types of surgeries, from 27.1% to 15.2% for herniorrhaphy (P = 0.005), 58.3-40.0% for gastrectomy (P = 0.03), 50.0-4.1% for total gastrectomy (P = 0.12), 65.6-45.0% for colectomy (P = 0.004), 67.8-43.2% for high anterior resection (P = 0.02) and 69.6-47.9% for low anterior resection (P = 0.03). The adherence to briefing and debriefing were improved, and majority of the surgeons favored the bundle elements. CONCLUSIONS: The KAIZEN initiative was effective in clinical healthcare settings. In the event of scaling-up this initiative, the educational program for physicians should include project management strategies and leadership skills.

Learning Curve Analysis to Determine Operative Requirements for Young Vascular Surgeons Learning Open Abdominal Aortic Aneurysm Repair.

BACKGROUND: Since endovascular aneurysm repair has become predominant, the issue of training young vascular surgeons in open abdominal aortic aneurysm (AAA) surgery has received significant attention. Through learning curve analysis, we aimed to determine the number of cases needed for young surgeons to achieve satisfactory open surgical skills.Methods and Results:A total of 562 consecutive patients who underwent open repair either by an attending surgeon (group A) or 6 young vascular surgeons (group Y) were included and assessed with regards to the preparation, clamp, and total operation times. Although some of the patients' characteristics were different, the surgical procedures were comparable between the 2 groups. There was a clear trend towards a decrease in each 10 successive cases in group Y. The operation times in group A were constant at 72±30 (preparation), 48±10 (clamp), and 231±59 min (total), which were achieved by young vascular surgeons in 10, 30, and 10 cases, respectively. In the cumulative sum analysis, 25-27 cases were necessary for young vascular surgeons to enhance their surgical skills. The complication rate in group Y was no higher than that in group A. CONCLUSIONS: Young vascular surgeons can safely learn open AAA repair without increasing operation time or complications. Approximately 30 cases would be necessary to gain satisfactory surgical skills.

Lower risk of postoperative delirium using laparoscopic approach for major abdominal surgery.

BACKGROUND: A laparoscopic approach is increasingly being used for major abdominal surgeries and is reportedly associated with a lower incidence of postoperative complications. However, the association of laparoscopic approach and postoperative delirium remains unclear. We aimed to retrospectively investigate risk factors for postoperative delirium after abdominal surgery particularly assessing the association between a laparoscopic approach and postoperative delirium. METHODS: We retrospectively studied 801 patients who underwent major abdominal surgery between April 2012 and December 2013. Among these, 181 (22.6%) patients underwent a laparoscopic and 620 (77.4%) patients underwent an open procedure. A Cox proportional hazard model analysis was used to identify risk factors for the development of postoperative delirium or overall survival within 180 days after surgery. Cumulative incidence of postoperative delirium was assessed using a propensity score-matching analysis. RESULTS: Postoperative delirium occurred in 56 patients (7.0%). A Multivariate Cox proportional hazard model analysis revealed that a laparoscopic approach reduced the risk of postoperative delirium [hazard ratio (HR) 0.30, 95% confidence interval (CI) 0.07-0.84, p = 0.019]. Postoperative delirium was associated with worse overall survival within 180 days (HR 4.91, 95% CI 1.96-12.22, p = 0.001) after adjusting for other confounders using the Cox proportional hazard model analysis. Patients who developed postoperative delirium showed worse outcomes including higher rate of morbidity except delirium (p < 0.001), longer hospitalization (p < 0.001), and post-discharge institutionalization (p < 0.001). After propensity score-matching, cumulative incidence rates of postoperative delirium were significantly lower in the laparoscopic group compared to the open group (30-day cumulative incidence rate, 1.7% vs. 7.8%, p = 0.006). CONCLUSIONS: The risk of postoperative delirium after major abdominal surgery is reduced using laparoscopic approach. Postoperative delirium should be prevented as it precipitates adverse postoperative events.

Prediction of human pharmacokinetics of typical compounds by a physiologically based method using chimeric mice with humanized liver.

In this study, total body clearance (CLt), volume of distribution at steady state (Vss) and plasma concentration-time profiles in humans of model compounds were predicted using chimeric mice with humanized livers. On the basis of assumption that unbound intrinsic clearance (CLUint) per liver weight in chimeric mice was equal to those in humans, CLt were predicted by substituting human liver blood flow and liver weights in well-stirred model. Vss were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SFKp) in chimeric mice estimated from a difference between the observed and predicted Vss. These physiological approaches showed high prediction accuracy for CLt and Vss values in humans. We compared the predictability of CLt and Vss determined by the physiologically based predictive approach using chimeric mice with those from predictive methods reported by Pharmaceutical Research Manufacturers of America. The physiological approach using chimeric mice indicated the best prediction accuracy in each predictive method. Simulation of human plasma concentration-time profiles were generally successful with physiologically based pharmacokinetic (PBPK) model incorporating CLUint and SFKp obtained from chimeric mice. Combined application of chimeric mice and PBPK modeling is effective for prediction of human PK in various compounds.

Factors Affecting Longer Stay and Higher Costs during Elective Open Repair for Abdominal Aortic Aneurysm: A Case-Control Study.

BACKGROUND: Open surgery for abdominal aortic aneurysm (AAA) has the advantage of requiring less reintervention compared with endovascular aneurysm repair. The reduction of the initial hospitalization costs can provide socioeconomic benefits. The objective of this study was to determine the factors associated with an increase in the length of hospital stay and costs of open surgery for AAA. METHODS: A total of 579 consecutive patients who underwent open surgery for intact AAA and survived, between 1998 and 2015 at Asahi General Hospital in Japan, were included in the analysis. Patients' characteristics, aneurysm morphology, operative procedures, postoperative complications, and postoperative courses were analyzed in relation to the hospital length of stay and costs. Patients with longer stays or higher costs (exceeding the third quartile) were compared with those with stays or costs no more than the third quartile. RESULTS: The mean patient age was 75 ± 8 years, and 492 patients (85%) were male, with a mean aortic diameter of 57 ± 10 mm. The mean operation time was 214 ± 56 min with an estimated mean blood loss of 444 ± 305 g. Transfusion was required in 28 patients (4.8%) and return to the operating room (RTOR) in 18 patients (3.1%). The median postoperative hospital stay was 7 (7-8) days. Median costs of hospitalization were 12,300 (11,800-13,100) United States Dollar. In the multivariate analysis, the major factors which increased the length of stay were transfusion, late ambulation, and prolonged fasting time. Major risk factors for higher total hospitalization costs were transfusion, RTOR, and longer fasting time. CONCLUSIONS: Regardless of the patients' comorbidities or aneurysm morphology, avoidance of transfusion and RTOR, combined with early ambulation and enteral feeding in the postoperative care, can reduce the length of stay and total hospitalization costs associated with open surgery for AAA.

Development and validation of a nomogram predicting postoperative pneumonia after major abdominal surgery.

PURPOSE: Postoperative pneumonia (POP) is a common complication that can adversely affect the outcomes after surgery. This study aimed to devise and validate a model for stratifying the probability of POP in patients undergoing abdominal surgery. METHODS: We included 1050 patients who underwent major abdominal surgery between 2012 and 2013. A nomogram was devised by evaluating the predictive factors for POP. RESULTS: Of the 1050 patients, 56 (5.3%) developed POP. Multivariable logistic regression analysis revealed that the independent predictive factors for POP were age, male sex, history of cerebrovascular disease, Brinkman Index (BI) ≥ 900, and upper midline incision. A nomogram was devised by employing these five significant predictive factors. The prediction model showed a relatively good discrimination performance, with a concordance index of 0.77. CONCLUSIONS: A nomogram based on age, male sex, history of cerebrovascular disease, BI ≥ 900, and upper midline incision may be useful for identifying patients with a high probability of developing POP after major abdominal surgery.

Deep neural network-based computer-assisted detection of cerebral aneurysms in MR angiography.

BACKGROUND: The usefulness of computer-assisted detection (CAD) for detecting cerebral aneurysms has been reported; therefore, the improved performance of CAD will help to detect cerebral aneurysms. PURPOSE: To develop a CAD system for intracranial aneurysms on unenhanced magnetic resonance angiography (MRA) images based on a deep convolutional neural network (CNN) and a maximum intensity projection (MIP) algorithm, and to demonstrate the usefulness of the system by training and evaluating it using a large dataset. STUDY TYPE: Retrospective study. SUBJECTS: There were 450 cases with intracranial aneurysms. The diagnoses of brain aneurysms were made on the basis of MRA, which was performed as part of a brain screening program. FIELD STRENGTH/SEQUENCE: Noncontrast-enhanced 3D time-of-flight (TOF) MRA on 3T MR scanners. ASSESSMENT: In our CAD, we used a CNN classifier that predicts whether each voxel is inside or outside aneurysms by inputting MIP images generated from a volume of interest (VOI) around the voxel. The CNN was trained in advance using manually inputted labels. We evaluated our method using 450 cases with intracranial aneurysms, 300 of which were used for training, 50 for parameter tuning, and 100 for the final evaluation. STATISTICAL TESTS: Free-response receiver operating characteristic (FROC) analysis. RESULTS: Our CAD system detected 94.2% (98/104) of aneurysms with 2.9 false positives per case (FPs/case). At a sensitivity of 70%, the number of FPs/case was 0.26. DATA CONCLUSION: We showed that the combination of a CNN and an MIP algorithm is useful for the detection of intracranial aneurysms. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:948-953.

Studies on the Unusual 1ß-Hydroxylated Bile Acid Biosynthesis in Infants.

Unusual bile acids (1ß-hydroxylated bile acids), particularly 1ß-hydroxyl-cholic acid (CA-1ß-ol) and 1ß-hydroxyl-chenodeoxycholic acid (CDCA-1ß-ol), have been detected in the urine of infants. These acids are conjugated with amino acids, such as taurine, and are then excreted mainly via the urine. CA-1ß-ol and CDCA-1ß-ol are the predominant bile acids during infancy and are present in relatively large amounts in the urine. However, the biosynthetic pathway of 1ß-hydroxylated bile acids in infants remains unclear. To investigate the biosynthetic pathway of 1ß-hydroxylated bile acids during infancy, we performed a metabolic reaction using infant hepatocytes at 3 months after delivery. Glyco- and tauro-CA-1ß-ol were identified by LC/tandem mass spectrometry (MS/MS) analysis of the extracted culture medium incubated with cholic acids (CAs). Further, we identified that ketoconazole suppressed CA 1ß-hydroxylation and that the CYP3A subfamily was the primary group of enzymes responsible for CA-1ß-ol formation. The present study provides new information about the biosynthetic pathway of 1ß-hydroxylated bile acids during infancy.

Insufficient Lymph Node Sampling in Patients with Colorectal Cancer Perforation is Associated with an Adverse Oncological Outcome.

BACKGROUND: The impact of lymph node (LN) dissection on long-term outcomes for patients with colorectal cancer (CRC) perforation remains unclear. We aim to investigate factors associated with poor prognosis and recurrence in patients with CRC, with special reference to cancer perforation and LN dissection. METHODS: The subjects comprised 550 patients who underwent colorectal surgery for CRC at Stage II or III (TNM classification) between February 2006 and November 2013. Short- and long-term outcomes of patients with or without CRC perforation were evaluated. We also sought risk factors on poor prognosis, focusing on LN dissection in patients with CRC perforation. RESULTS: A total of 508 underwent surgery for CRC without perforation (the non-perforation group) and 39 for CRC with perforation (the perforation group). Both overall survival and recurrence-free survival rates were significantly lower in the perforation group than in the non-perforation group (overall survival, P = 0.009; recurrence-free survival, P < 0.001). The relapse rates at the peritoneum (P = 0.002), lung (P = 0.007) and LNs (P = 0.021) were significantly higher in the perforation group than in the non-perforation group. Multivariable Cox proportional hazards model revealed that CRC perforation (hazard ratio [HR] 2.55, 95 % confidential interval [CI] 1.16-4.98, P = 0.022), LN dissection <12 (HR 1.83, 95 % CI 1.07-3.13, P = 0.027), and Stage III (HR 1.79, 95 % CI 1.06-3.08, P = 0.031) were significant and independent risk factors for poor prognosis. CONCLUSIONS: Conducting <12 LN dissections independently increased the risk of reduction in overall survival for patients with CRC perforation. Thus, radical LN dissections should be performed to improve patients' survival rates, when patients' general and surgical conditions allow.