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The musculoskeletal system around the human hip joint has acquired a suitable structure for erect bipedal walking. However, little is known about the process of separation and maturation of individual muscles during the prenatal period, when muscle composition is acquired. Understanding the maturation process of the normal musculoskeletal system contributes to elucidating the acquisition of bipedal walking in humans and to predicting normal growth and detecting congenital muscle disorders and anomalies. In this study, we clarify the process of thigh muscle maturation from the embryonic stage to the mid-fetal stage using serial sections, phase-contrast X-ray computed tomography, and magnetic resonance imaging. We also provide a 4D atlas of human thigh muscles between 8 and 23 weeks of gestation. As a result, we first show that muscle separation in the lower thigh tends to progress from the superficial to the deep layers and that all musculoskeletal components are formed by Carnegie Stage 22. Next, we show that femur and muscle volume grow in correlation with crown-rump length. Finally, we show that the anterior, abductor, and posterior muscle groups in the thigh contain a high percentage of monoarticular muscle volume by the end of the embryonic period. This ratio approaches that of adult muscle composition during normal early fetal development and is typical of bipedal walking. This study of fetal muscle composition suggests that preparation for postnatal walking may begin in early fetal period.

To examine the value of 3-T MRI for evaluating the difference between the pancreatic parenchyma of intraductal papillary mucinous neoplasm with a concomitant invasive carcinoma (IPMN-IC) and the pancreatic parenchyma of patients without an IPMN-IC.A total of 132 patients underwent abdominal 3-T MRI. Of the normal pancreatic parenchymal measurements, the pancreas-to-muscle signal intensity ratio in in-phase imaging (SIR-I), SIR in opposed-phase imaging (SIR-O), SIR in T2-weighted imaging (SIR-T2), ADC (×10No significant differences were observed among the three groups in age, sex, body mass index, prevalence of diabetes mellitus, and hemoglobin A1c (p = 0.141 to p = 0.657). In comparisons among the three groups, the PDFF showed a significant difference (p0.001), and there were no significant differences among the three groups in SIR-I, SIR-O, SIR-T2, and ADC (p = 0.153 to p = 0.684). The PDFF of the pancreas was significantly higher in the IPMN-IC group than in the normal pancreas group or the IPMN group (p0.001 and p0.001, respectively), with no significant difference between the normal pancreas group and the IPMN group (p = 0.916).These observations suggest that the PDFF of the pancreas is associated with the presence of IPMN-IC.• The cause and risk factors of IPMN with a concomitant invasive carcinoma have not yet been clarified. • The PDFF of the pancreas was significantly higher in the IPMN-IC group than in the normal pancreas group or the IPMN group. • Pancreatic PDFF may be a potential biomarker for the development of IPMN with a concomitant invasive carcinoma.

Penile cancer is a rare cancer for which no medical guidelines have been established before in Japan. These guidelines aim to standardize, as much as possible, the therapeutic modality for penile cancer, for which empirical evidence is limited on a global scale, thereby bolstering therapeutic outcomes for patients with penile cancer. The new guidelines conform to the Minds Guide for Developing Clinical Practice Guidelines (2017) as much as possible. However, virtually no randomized comparative studies and meta-analyses based on such randomized studies have been conducted. Therefore, only the findings available at present were listed after conducting an exhaustive literature review of items with extremely low evidence levels and for which bodies of evidence and grades of recommendation were not evaluated. Clinical questions were set for items with a relatively large number of studies, including retrospective studies. However, since it is virtually impracticable to summarize bodies of evidence by systematic reviews, recommendation grades and evidence levels were discussed and determined by the consensus panel of the Preparatory Committee. The following were outlined: epidemiological, pathological, diagnostic, therapeutic, follow-up, and quality of life-related findings. Additionally, seven clinical questions were established to determine recommendation grades and evidence levels. We hope that these guidelines will prove to be useful to medical professionals engaged in clinical practice related to penile cancer in Japan and anticipate that critical reviews of the guidelines will lead to further refinement of the next edition.

Objective Mapping the long-term prognosis of Budd-Chiari syndrome (BCS) is difficult, as the prognosis is associated with changes in the liver function. The present study evaluated the time course changes in the liver function in a treatment group with percutaneous old balloon angioplasty (POBA) and a non-treatment group using the albumin-bilirubin score (ALBI) and Child-Pugh score during long-term follow-up. Methods In this retrospective study, 13 consecutive patients diagnosed with BCS at our hospital between 2007 and 2020 were categorized into a treatment group (n=8), which received POBA, and a non-treatment group (n=5). Differences in the liver function in the ALBI and Child-Pugh scores between the initial visit and one- and three-year follow-up were calculated and statistically evaluated. We investigated the changes in the liver function during the long-term follow-up, including events such as re-stenosis and re-treatment. Results While the Child-Pugh scores in the treatment group did not differ significantly between the initial visit and 1- or 3-year follow-up, the ALBI scores in this group improved significantly between the initial visit and the 1- or 3-year follow-up visit (p=0.0078 and 0.0156, respectively). The liver function according to the ALBI score in the treatment group showed gradual improvement from the initial value but gradual worsening in the non-treatment group. The ALBI scores also revealed that the liver function varies according to re-stenosis and re-POBA in BCS patients. Conclusion Unlike the Child-Pugh score, the ALBI score was able to capture changes in the liver function of BCS patients during the long-term course of BCS.

OBJECTIVE: High b-value diffusion-weighted imaging (hDWI) with a b-value of 2000 s/mm(2) provides insufficient image contrast between benign and malignant tissues and an overlap of apparent diffusion coefficient (ADC) between Gleason grades (GG) in prostate cancer (PC). We compared image quality, PC detectability, and discrimination ability for PC aggressiveness between ultra-high b-value DWI (uhDWI) of 3000 s/mm(2) and hDWI. METHODS: The subjects were 49 patients with PC who underwent 3T multiparametric MRI. Single-shot echo-planar DWI was acquired with b-values of 0, 2000, and 3000 s/mm(2). Anatomical distortion of prostate (AD), signal intensity of benign prostate (PSI), and lesion conspicuity score (LCS) were assessed using a 4-point scale; and signal-to-noise ratio, contrast-to-noise ratio, and mean ADC (×10(–3) mm(2)/s) of lesion (lADC) and surrounding benign region (bADC) were measured. RESULTS: PSI was significantly lower in uhDWI than in hDWI (p < 0.001). AD, LCS, signal-to-noise ratio, and contrast-to-noise ratio were comparable between uhDWI and hDWI (all p > 0.05). In contrast, lADC was significantly lower than bADC in both uhDWI and hDWI (both p < 0.001). In comparison of lADC between tumors of ≤GG2 and those of ≥GG3, both uhDWI and hDWI showed significant difference (p = 0.007 and p = 0.021, respectively). AUC for separating tumors of ≤GG2 from those of ≥GG3 was 0.731 in hDWI and 0.699 in uhDWI (p = 0.161). CONCLUSION: uhDWI suppressed background signal better than hDWI, but did not contribute to increased diagnostic performance in PC. ADVANCES IN KNOWLEDGE: Compared with hDWI, uhDWI could not contribute to increased diagnostic performance in PC.

PURPOSE The molecular subtype of breast cancer is an important component of establishing the appropriate treatment strategy. In clinical practice, molecular subtypes are determined by receptor expressions. In this study, we developed a model using deep learning to determine receptor expressions from mammograms. METHODS A developing data set and a test data set were generated from mammograms from the affected side of patients who were pathologically diagnosed with breast cancer from January 2006 through December 2016 and from January 2017 through December 2017, respectively. The developing data sets were used to train and validate the DL-based model with five-fold cross-validation for classifying expression of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2-neu (HER2). The area under the curves (AUCs) for each receptor were evaluated with the independent test data set. RESULTS The developing data set and the test data set included 1,448 images (997 ER-positive and 386 ER-negative, 641 PgR-positive and 695 PgR-negative, and 220 HER2-enriched and 1,109 non–HER2-enriched) and 225 images (176 ER-positive and 40 ER-negative, 101 PgR-positive and 117 PgR-negative, and 53 HER2-enriched and 165 non–HER2-enriched), respectively. The AUC of ER-positive or -negative in the test data set was 0.67 (0.58-0.76), the AUC of PgR-positive or -negative was 0.61 (0.53-0.68), and the AUC of HER2-enriched or non–HER2-enriched was 0.75 (0.68-0.82). CONCLUSION The DL-based model effectively classified the receptor expressions from the mammograms. Applying the DL-based model to predict breast cancer classification with a noninvasive approach would have additive value to patients.

Purpose To compare diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MR imaging (DCE-MRI) for characterization of prostate cancer (PC). Methods 104 PC patients who underwent prostate multiparametric MRI at 3T including DWI and DCE-MRI before MRI-guided biopsy or radical prostatectomy. Apparent diffusion coefficient (ADC) with histogram analysis (mean, 0–25th percentile, skewness, and kurtosis), intravoxel incoherent motion model including D and f; stretched exponential model including distributed diffusion coefficient (DDC) and a; and permeability parameters including Ktrans, Kep, and Ve were obtained from a region of interest placed on the dominant tumor of each patient. Results ADCmean, ADC0–25, D, DDC, and Ve were significantly lower and Kep was significantly higher in GS ≥ 3 + 4 tumors (n = 89) than in GS = 3 + 3 tumors (n = 15), and also in GS ≥ 4 + 3 tumors (n = 57) than in GS ≤ 3 + 4 tumors (n = 47) (P 0.80, there was a significant difference in AUC between ADC0–25 and D, and DDC for separating GS ≤ 3 + 4 tumors from GS ≥ 4 + 3 tumors (P = 0.040 and P = 0.022, respectively). There were no significant differences between metrics with AUC > 0.80 for separating GS = 3 + 3 tumors from GS ≥ 3 + 4 tumors. ADC0–25 had the highest correlation with Gleason grade (ρ = −0.625, P Conclusions DWI and DCE-MRI showed no apparent clinical superiority of non-Gaussian models or permeability MRI over the mono-exponential model for assessment of tumor aggressiveness in PC.

Background We investigated the performance improvement of physicians with varying levels of chest radiology experience when using a commercially available artificial intelligence (AI)-based computer-assisted detection (CAD) software to detect lung cancer nodules on chest radiographs from multiple vendors. Methods Chest radiographs and their corresponding chest CT were retrospectively collected from one institution between July 2017 and June 2018. Two author radiologists annotated pathologically proven lung cancer nodules on the chest radiographs while referencing CT. Eighteen readers (nine general physicians and nine radiologists) from nine institutions interpreted the chest radiographs. The readers interpreted the radiographs alone and then reinterpreted them referencing the CAD output. Suspected nodules were enclosed with a bounding box. These bounding boxes were judged correct if there was significant overlap with the ground truth, specifically, if the intersection over union was 0.3 or higher. The sensitivity, specificity, accuracy, PPV, and NPV of the readers’ assessments were calculated. Results In total, 312 chest radiographs were collected as a test dataset, including 59 malignant images (59 nodules of lung cancer) and 253 normal images. The model provided a modest boost to the reader’s sensitivity, particularly helping general physicians. The performance of general physicians was improved from 0.47 to 0.60 for sensitivity, from 0.96 to 0.97 for specificity, from 0.87 to 0.90 for accuracy, from 0.75 to 0.82 for PPV, and from 0.89 to 0.91 for NPV while the performance of radiologists was improved from 0.51 to 0.60 for sensitivity, from 0.96 to 0.96 for specificity, from 0.87 to 0.90 for accuracy, from 0.76 to 0.80 for PPV, and from 0.89 to 0.91 for NPV. The overall increase in the ratios of sensitivity, specificity, accuracy, PPV, and NPV were 1.22 (1.14–1.30), 1.00 (1.00–1.01), 1.03 (1.02–1.04), 1.07 (1.03–1.11), and 1.02 (1.01–1.03) by using the CAD, respectively. Conclusion The AI-based CAD was able to improve the ability of physicians to detect nodules of lung cancer in chest radiographs. The use of a CAD model can indicate regions physicians may have overlooked during their initial assessment.

Background and aims We developed a deep learning (DL) model for automated atherosclerotic plaque categorization using optical frequency domain imaging (OFDI) and performed quantitative and visual evaluations. Methods A total of 1103 histological cross-sections from 45 autopsy hearts were examined to compare the ex vivo OFDI scans. The images were segmented and annotated considering four histological categories: pathological intimal thickening (PIT), fibrous cap atheroma (FA), fibrocalcific plaque (FC), and healed erosion/rupture (HER). The DL model was developed based on pyramid scene parsing network (PSPNet). Given an input image, a convolutional neural network (ResNet50) was used as an encoder to generate feature maps of the last convolutional layer. Results For the quantitative evaluation, the mean F-score and IoU values, which are used to evaluate how close the predicted results are to the ground truth, were used. The validation and test dataset had F-score and IoU values of 0.63, 0.49, and 0.66, 0.52, respectively. For the section-level diagnostic accuracy, the areas under the receiver-operating characteristic curve produced by the DL model for FC, PIT, FA, and HER were 0.91, 0.85, 0.86, and 0.86, respectively, and were comparable to those of an expert observer. Conclusions DL semantic segmentation of coronary plaques in OFDI images was used as a tool to automatically categorize atherosclerotic plaques using histological findings as the gold standard. The proposed method can support interventional cardiologists in understanding histological properties of plaques.

Introduction: Lenvatinib has been approved as a systemic therapy for patients with unresectable hepatocellular carcinoma (HCC). We recently experienced lenvatinib-induced tumor-related hemorrhage in patients with HCC. The full details of tumor-related hemorrhage as a lenvatinib-related adverse event have not been elucidated. Methods: This was a retrospective single-center study that enrolled consecutive patients treated with lenvatinib for unresectable HCC from April 2018 to February 2020. Results: Sixty-eight consecutive patients were enrolled in this study. Among them, 5 cases developed intraperitoneal or intratumoral hemorrhages. The patients with hemorrhage had larger tumors (maximum tumor size, 97.5 ± 46.4 and 38.2 ± 28.8 mm, respectively; p = 0.009) than the patients without hemorrhage. The dosing period of lenvatinib (median, 3 and 93 days, respectively; p < 0.001) and the survival time from initial administration of lenvatinib (median, 77 and 495 days, respectively; p < 0.001) of the patients with hemorrhage were shorter than those of the patients without hemorrhage. Especially, in 4 cases with large HCCs (maximum tumor diameter was >90 mm), tumor hemorrhage with vascular lake-like phenomenon was evident, although most tumor blood flow was suppressed. Discussion/Conclusion: It becomes clear that lenvatinib treatment brings about tumor-related hemorrhages despite rapid suppression of tumor blood flow. We speculate that lenvatinib quickly blocks the feeding circulation, resulting in tumor hemorrhage by necrosis. Clinicians should pay careful attention to the development of life-threatening hemorrhages when treating large HCCs with lenvatinib.

Sudden infant death syndrome (SIDS) remains a leading cause of infant death in high-income countries. Supporting models for categorization of sudden unexpected infant death into SIDS/non-SIDS could reduce mortality. Therefore, we aimed to develop such a tool utilizing forensic data, but the reduced number of SIDS cases renders this task inherently difficult. To overcome this, we constructed Bayesian network models according to diagnoses performed by expert pathologists and created conditional probability tables in a proof-of-concept study. In the diagnostic support model, the data of 64 sudden unexpected infant death cases was employed as the training dataset, and 16 known-risk factors, including age at death and co-sleeping, were added. In the validation study, which included 8 new cases, the models reproduced experts’ diagnoses in 4 or 5 of the 6 SIDS cases. Next, to confirm the effectiveness of this approach for onset prediction, the data from 41 SIDS cases was employed. The model predicted that the risk of SIDS in 0- to 2-month-old infants exposed to passive smoking and co-sleeping is eightfold higher than that in the general infant population, which is comparable with previously published findings. The Bayesian approach could be a promising tool for constructing SIDS prevention models.

Background Pemafibrate, a selective PPARα modulator, has the beneficial effects on serum triglycerides (TGs) and very low density lipoprotein (VLDL), especially in patients with diabetes mellitus or metabolic syndrome. However, its effect on the low density lipoprotein cholesterol (LDL-C) levels is still undefined. LDL-C increased in some cases together with a decrease in TGs, and the profile of lipids, especially LDL-C, during pemafibrate administration was evaluated. Methods Pemafibrate was administered to type 2 diabetes patients with hypertriglyceridemia. Fifty-one type 2 diabetes patients (mean age 62 ± 13 years) with a high rate of hypertension and no renal insufficiency were analyzed. Pemafibrate 0.2 mg (0.1 mg twice daily) was administered, and serum lipids were monitored every 4–8 weeks from 8 weeks before administration to 24 weeks after administration. LDL-C was measured by the direct method. Lipoprotein fractions were measured by electrophoresis (polyacrylamide gel, PAG), and LDL-migration index (LDL-MI) was calculated to estimate small, dense LDL. Results Pemafibrate reduced serum TGs, midband and VLDL fractions by PAG. Pemafibrate increased LDL-C levels from baseline by 5.3% (− 3.8–19.1, IQR). Patients were divided into 2 groups: LDL-C increase of > 5.3% (group I, n = 25) and < 5.3% (group NI, n = 26) after pemafibrate. Compared to group NI, group I had lower LDL-C (2.53 [1.96–3.26] vs. 3.36 [3.05–3.72] mmol/L, P = 0.0009), higher TGs (3.71 [2.62–6.69] vs. 3.25 [2.64–3.80] mmol/L), lower LDL by PAG (34.2 [14.5, SD] vs. 46.4% [6.5], P = 0.0011), higher VLDL by PAG (28.2 [10.8] vs. 22.0% [5.2], P = 0.0234), and higher LDL-MI (0.421 [0.391–0.450] vs. 0.354 [0.341–0.396], P Conclusions Pemafibrate significantly reduced TGs, VLDL, midband, and small, dense LDL, but increased LDL-C in diabetes patients with higher baseline TGs and lower baseline LDL-C. Even if pre-dose LDL-C remains in the normal range, pemafibrate improves LDL composition and may reduce cardiovascular disease risk.

An 87-year-old man with hepatocellular carcinoma (HCC) presented with right-sided chest pain. Computed tomography revealed right bloody pleural effusion and an extravasation from an arterially enhanced mass in the right seventh posterior intercostal space. These findings indicated hemothorax from a rupture of HCC metastasis to the chest wall. Angiography of the intercostal arteries confirmed a hypervascular tumor, and transcatheter arterial embolization resulted in hemostasis. He was discharged with palliative care and remains alive after 9 months. Although hemothorax represents an unusual, life-threatening complication of HCC, our case suggests that transcatheter treatment can achieve hemostasis and a favorable survival even in elderly patients.

Purpose Portal venous system thrombosis is a complication of partial splenic artery embolization, and pre-treatment risk assessment is thus important. The purpose of this study was to identify the risk factors for portal venous system thrombosis after partial splenic artery embolization. Materials and methods We retrospectively analyzed 67 consecutive patients who underwent contrast-enhanced computed tomography before and after first partial splenic artery embolization between July 2007 and October 2018. As risk factors, we investigated age, sex, hematological data, liver function, steroid use, heparin use, and findings from pre- and post-treatment computed tomography. Uni- and multivariate analyses were performed to evaluate the relationship between thrombus appearance or growth and these factors. Values of p Results Partial splenic artery embolization was technically successful in all 67 patients. Nine patients showed appearance or growth of thrombus. Univariate analysis showed maximum diameter of the splenic vein before treatment (p = 0.0076), percentage of infarcted spleen (p = 0.017), and volume of infarcted spleen (p = 0.022) as significant risk factors. Multivariate analysis showed significant differences in maximum diameter of the splenic vein before treatment (p = 0.041) and percentage of infarcted spleen (p = 0.023). According to receiver operating characteristic analysis, cutoffs for maximum diameter of the splenic vein and percentage of infarcted spleen for distinguishing the appearance or growth of thrombus were 17 mm and 58.2%. Conclusion Large maximum diameter of the splenic vein before partial splenic artery embolization and high percentage of infarcted spleen after partial splenic artery embolization were identified as risk factors for portal venous system thrombosis. Level of Evidence Level 4, Case Series

Aim Precise biomarkers for predicting prognosis could help to identify high-risk Crohn's disease (CD) patients to facilitate better follow-up during the postoperative course. In this study, the primary aim is the identification of the most reliable nutrition marker that predicts surgical relapse in CD patients. Method We first evaluated the predictive value of various nutrition markers for postoperative surgical relapse in CD patients and identified the advanced lung cancer inflammation index (ALI) as a promising biomarker. Then, we assessed the clinical significance of preoperative ALI in CD patients using two cohorts. Results Preoperative ALI showed the highest correlation with reoperation rate compared with other nutritional parameters in CD patients receiving surgical resection (sensitivity 53%, specificity 86%, area under the curve 0.71). Lower levels of preoperative ALI were significantly correlated with the presence of perianal disease. A lower level of preoperative ALI was an independent prognostic factor for reoperation rate after an intestinal resection (hazard ratio 3.37, 95% CI 1.38-10.12, P = 0.006), and the prognostic impact of preoperative ALI was successfully validated in an independent cohort using the same cut-off value. Conclusion Preoperative ALI might be useful for postoperative management of CD patients.

Bone metastases can cause high morbidity and mortality, often developing as they advance, especially in patients with prostate and breast cancers. Most drugs are rarely distributed to the bone and are hence pharmacologically ineffective in treating bone metastases. The development of drug targeting technologies is required for the efficient treatment of bone metastases. To date, numerous bone-targeting ligands, including tetracyclines, bisphosphonates, aspartic acid, and aptamers have been developed and used for bone-targeted delivery of anti-tumor drugs, peptide/protein drugs, nucleic acid drugs, and diagnostic imaging agents. The conjugates of drugs with bone-targeting ligands were first developed in the field of bone drug targeting systems; macromolecular carriers and nanoparticles modified with these bone-targeting ligands have also been developed. Additionally, antibodies to prostate-specific membrane antigen (PSMA) and human epidermal growth factor receptor 2 (HER2) are used in active targeting bone metastatic prostate cancer and breast cancer, respectively. Some conjugates using antibodies to PSMA and HER2 were developed and used in clinical trials. In this review, recent challenges in the development of bone-targeted delivery systems and strategies for the treatment of bone metastasis have been summarized. Future development of novel drug formulations in order to optimize targeted drug delivery in the treatment of bone metastasis have also been discussed.

Background/aim There is rapid progression and widespread use of patient-derived tumor xenografts (PDX) in translational pancreatic cancer research. This study aimed to establish a liver transplant PDX model using cryopreserved primary pancreatic ductal adenocarcinoma (PDAC). Patients and methods Primary PDAC from 10 patients were cryopreserved and transplanted into immunodeficient mice using the liver pocket method. H&E staining and immunohistochemical staining, such as Ki-67, p53, Smad4, and MUC1 were used to evaluate engraftment and histological similarities. Results Patient-derived xenograft placement was successful in six cases (60%), and 10 mice (33.3%). The Ki-67 index of primary PDAC and the cryopreservation duration were significantly related to successful engraftment (p=0.003 and p=0.007, respectively). Conclusion In this study, we succeeded in establishing a liver transplant PDX mouse model as a preclinical platform. The successful engraftment was affected by the cryopreservation duration and could be detected by the Ki-67 index.

Breast cancer resistance protein (BCRP) is expressed on the apical membrane of small intestinal epithelial cells and functions as an efflux pump with broad substrate recognition. Therefore, quantitative evaluation of the contribution of BCRP to the intestinal permeability of new chemical entities is very important in drug research and development. In this study, we assessed the BCRP-mediated efflux of several model drugs in Caco-2 cells using WK-X-34 as a dual inhibitor of P-glycoprotein (P-gp) and BCRP and LY335979 as a selective inhibitor of P-gp. The permeability of daidzein was high with an apparent permeability coefficient for apical-to-basal transport (PAB) of 20.3 × 10−6 cm/s. In addition, its efflux ratio (ER) was 1.55, indicating that the contribution of BCRP to its transport is minimal. Estrone-3-sulfate and ciprofloxacin showed relatively higher ER values (>2.0), whereas their BCRP-related absorptive quotient (AQBCRP) was 0.21 and 0.3, respectively. These results indicate that BCRP does not play a major role in regulating the permeability of estrone-3-sulfate and ciprofloxacin in Caco-2 cells. Nitrofurantoin showed a PAB of 1.8 × 10−6 cm/s, and its ER was 7.6. However, the AQBCRP was 0.37, suggesting minimal contribution of BCRP to nitrofurantoin transport in Caco-2 cells. In contrast, topotecan, SN-38, and sulfasalazine had low PAB values (0.81, 1.13, and 0.19 × 10−6 cm/s, respectively), and each AQBCRP was above 0.6, indicating that BCRP significantly contributes to the transport of these compounds in Caco-2 cells. In conclusion, Caco-2 cells are useful to accurately estimate the contribution of BCRP to intestinal drug absorption. SIGNIFICANCE STATEMENT We performed an in vitro assessment of the contribution of breast cancer resistance protein (BCRP) to the transport of BCRP and/or P-glycoprotein (P-gp) substrates across Caco-2 cell monolayers using absorptive quotient, which has been proposed to represent the contribution of drug efflux transporters to the net efflux. The present study demonstrates that the combined use of a BCRP/P-gp dual inhibitor and a P-gp selective inhibitor is useful to estimate the impact of BCRP and P-gp on the permeability of tested compounds in Caco-2 cells.

Understanding a drug candidate’s pharmacokinetic (PK) parameters is a challenging but essential aspect of drug development. Investigating the penetration and distribution of a topical drug’s active pharmaceutical ingredient (API) allows for evaluating drug delivery and efficacy, which is necessary to ensure drug viability. A topical gel (BPX-05) was recently developed to treat moderate to severe acne vulgaris by directly delivering the combination of the topical antibiotic minocycline and the retinoid tazarotene to the pilosebaceous unit of the dermis. In order to evaluate the uptake of APIs within human facial skin and confirm accurate drug delivery, a selective visualization method to monitor and quantify local drug distributions within the skin was developed. This approach uses fluorescence lifetime imaging microscopy (FLIM) paired with a multicomponent phasor analysis algorithm to visualize drug localization. As minocycline and tazarotene have distinct fluorescence lifetimes from the lifetime of the skin’s autofluorescence, these two APIs are viable targets for distinct visualization via FLIM. Here, we demonstrate that the analysis of the resulting FLIM output can be used to determine local distributions of minocycline and tazarotene within the skin. This approach is generalizable and can be applied to many multicomponent fluorescence lifetime imaging targets that require cellular resolution and molecular specificity.

There are still no useful predictive biomarkers for esophago-gastric junction (EGJ) cancer. We compared 15 candidate inflammation-based markers and investigated the clinical impact of the selected biomarker.One hundred three patients with EGJ cancer between 2002 and 2020 were enrolled, and associations between clinicopathological data and inflammatory biomarkers were retrospectively analyzed. Area under the curve (AUC) values of 15 candidate biomarkers were compared in receiver operating characteristic (ROC) curves regarding overall survival (OS). Clinical impacts of the selected marker were further investigated regarding long-term prognosis, postoperative complications, and preoperative chemotherapy effects.Lymphocyte/CRP ratio (LCR) demonstrated the highest AUC (0.68552) and was chosen as a candidate biomarker. The high LCR group (LCR4610) demonstrated significantly better OS (p 0.0001) and relapse-free survival (RFS) (p 0.0001) compared with the low LCR group (LCR ≤4610), and preoperative LCR was an independent prognostic factor for both OS (HR 4.97, 95% CI:2.24-11.58; p 0.0001) and RFS (HR 2.84, 95% CI:1.33-6.14, p = 0.007) in EGJ cancer patients. Another cut-off value was established for postoperative complications, and the incidence rates were significantly higher in the low LCR group (LCR ≤12000) than in the high LCR group (LCR12000) for all postoperative complications, infectious complications, and surgical site infection (p = 0.013, p = 0.016, and p = 0.030, respectively). Furthermore, patients with decreased LCR after preoperative chemotherapy demonstrated significantly worse RFS compared with patients with increased LCR (p = 0.043).LCR is a potential biomarker to predict long-term prognosis as well as occurrence of postoperative complications in patients with EGJ cancer.

In prostate MRI, single-shot EPI (ssEPI) DWI still suffers from distortion and blurring. Multi-shot EPI (msEPI) overcomes the drawbacks of ssEPI DWI. The aim of this article was to compare the image quality and diagnostic performance for clinically significant prostate cancer (csPC) between ssEPI DWI and msEPI DWI. This retrospective study included 134 patients with suspected PC who underwent 3.0 T MRI and subsequent MRI-guided biopsy. Three radiologists independently assessed anatomical distortion, prostate edge clarity, and lesion conspicuity score for pathologically confirmed csPC. Lesion apparent diffusion coefficient (ADC) and benign ADC were also calculated. In 17 PC patients who underwent prostatectomy, three radiologists independently assessed eight prostate regions by DWI score in PI-RADS v 2.1. Anatomical distortion and prostate edge clarity were significantly higher in msEPI DWI than in ssEPI DWI in the three readers. Lesion conspicuity score was significantly higher in msEPI DWI than in ssEPI DWI in reader 1 and reader 3. Regarding discrimination ability between PC with GS ≤ 3 + 4 and PC with GS ≥ 4 + 3 using lesion ADC, AUC was comparable between ssEPI DWI and msEPI DWI. For diagnostic performance of csPC using DWI score, AUC was comparable between msEPI DWI and ssEPI DWI in all readers. Compared with ssEPI DWI, msEPI DWI had improved image quality and similar or higher diagnostic performance.

To evaluate visually and quantitatively the performance of a deep-learning-based super-resolution (SR) model for microcalcifications in digital mammography.Mammograms were consecutively collected from 5080 patients who underwent breast cancer screening from January 2015 to March 2017. Of these, 93 patients (136 breasts, mean age, 50 ± 7 years) had microcalcifications in their breasts on mammograms. We applied an artificial intelligence model known as a fast SR convolutional neural network to the mammograms. SR and original mammograms were visually evaluated by four breast radiologists using a 5-point scale (1: original mammograms are strongly preferred, 5: SR mammograms are strongly preferred) for the detection, diagnostic quality, contrast, sharpness, and noise of microcalcifications. Mammograms were quantitatively evaluated using a perception-based image-quality evaluator (PIQE).All radiologists rated the SR mammograms better than the original ones in terms of detection, diagnostic quality, contrast, and sharpness of microcalcifications. These ratings were significantly different according to the Wilcoxon signed-rank test (p .001), while the noise score of the three radiologists was significantly lower (p .001). According to PIQE, SR mammograms were rated better than the original mammograms, showing a significant difference by paired t-test (p .001).An SR model based on deep learning can improve the visibility of microcalcifications in mammography and help detect and diagnose them in mammograms.

We aimed to investigate the difference in engraftment rates depending on the transplant site for a patient-derived xenograft (PDX) of pancreatic ductal adenocarcinoma (PDAC) and the effects of the microenvironment on engraftment.Frozen cancer tissues from PDAC tumors were used, and tumor fragments were directly implanted into the subcutaneous, orthotopic pancreas, peritoneum, and liver of X-linked severe combined immunodeficiency (XSCID) rats. We assessed the success of engraftment in each organ. Additionally, to evaluate the effect of the microenvironment in each organ, we performed immunohistochemical analysis.Subcutaneous transplantation was successful in 8 of 10 PDAC cases (16 of 30 rats). This was a higher rate than for other organ transplants. The vascular endothelial cells in the stroma were replaced with those from rats instead of humans. Vascular endothelial growth factor-A (VEGF-A) and cluster of differentiation-31 (CD31) was significantly more strongly expressed in the subcutaneous transplantation model (VEGF-A: p0.001, CD31: p=0.0036).The engraftment rate was significantly higher for the subcutaneous PDX model than for the orthotopic pancreatic, peritoneal, and liver PDX models. Blood vessels of the PDX stroma had been replaced by rat-derived vessels instead of the original human vessels, suggesting that angiogenesis in the PDX microenvironment may be a major factor in engraftment.

We recently reported evidence of transthyretin (TTR) familial amyloid polyneuropathy (TTR FAP) associated with TTR E61K, which is characterized by late-onset sensory dominant polyneuropathy, autonomic disturbances, and cardiomyopathy. In those TTR FAP patients, no amyloid deposits were observed in the endoneurium of examined sural nerves. Furthermore, the amyloidogenicity of E61K TTR was similar to that of wild-type TTR in vitro. Thus, we speculated that dorsal root ganglia (DRGs) may be the initial sites for the lesions in amyloid neuropathy because there is no blood-nerve barrier. In the present study, lumbar magnetic resonance imaging was performed to evaluate the DRGs in pre-symptomatic TTR E61K and V30M subjects. Magnetic resonance imaging (3 T) was used for three-dimensional T2-weighted imaging (coronal sections; slice thickness, 2 mm), and the DRG volumes were measured. The mean volumes of the bilateral L3, L4, and S1 DRGs in the pre-symptomatic TTR E61K subject were larger than those for the pre-symptomatic TTR V30M subject and five control patients. The mean volumes of the bilateral L4 to S1 DRGs in the pre-symptomatic TTR V30M subject were similar to those in control patients. A number of lumbar DRGs were enlarged in the pre-asymptomatic TTR E61K subject, suggesting that DRGs may be the sites of the initial lesions in the peripheral nervous system of this FAP.

We herein report a 61-year-old man who sustained injury after a 2-m fall and developed mediastinitis. He presented to another hospital two days after the fall and was transferred to our hospital four days after the fall with a fever and dysphagia. Computed tomography revealed osteophytes on the second and third thoracic vertebrae and free air in the mediastinum, indicating esophageal perforation. Emergent surgery was performed. Intraoperatively, a longitudinal esophageal tear was identified. We stress the importance of being aware of the possibility of osteophyte-related esophageal perforation in patients with a history of a fall. A delayed diagnosis affects the prognosis.

We developed and validated a deep learning (DL)-based model using the segmentation method and assessed its ability to detect lung cancer on chest radiographs. Chest radiographs for use as a training dataset and a test dataset were collected separately from January 2006 to June 2018 at our hospital. The training dataset was used to train and validate the DL-based model with five-fold cross-validation. The model sensitivity and mean false positive indications per image (mFPI) were assessed with the independent test dataset. The training dataset included 629 radiographs with 652 nodules/masses and the test dataset included 151 radiographs with 159 nodules/masses. The DL-based model had a sensitivity of 0.73 with 0.13 mFPI in the test dataset. Sensitivity was lower in lung cancers that overlapped with blind spots such as pulmonary apices, pulmonary hila, chest wall, heart, and sub-diaphragmatic space (0.50–0.64) compared with those in non-overlapped locations (0.87). The dice coefficient for the 159 malignant lesions was on average 0.52. The DL-based model was able to detect lung cancers on chest radiographs, with low mFPI.

A large rubella epidemic is currently ongoing since 2018 in Osaka, Japan. The detected rubella viruses were classified into genotypes 1E lineage 2 and 2B lineage 1. These strains may have been imported from endemic countries, and these viruses spread within the susceptible population.

Objective: To evaluate time-dependent changes in hepatic extracellular volume (ECV) fraction using contrast-enhanced CT (CECT) and serological liver fibrosis markers, the fibrosis-4 (FIB-4) index and aspartate aminotransferase to platelet ratio index (APRI), before and after direct-acting antiviral therapy (DAA) for hepatitis C virus (HCV) infection. Methods: 41 HCV-infected patients who achieved sustained virological response (SVR) after DAA (SVR group) and 10 control patients (untreated or unresponsive to treatment) who underwent CECT and serum biochemical tests before or after the first examination/DAA (T1) and at intervals thereafter (T2:24 months) were evaluated. Results: In the control group, ECV fractions remained relatively unchanged through the study, and significant differences in FIB-4 index comparisons and APRI comparisons were only seen between the T2 and T4 values (p = 0.046 and p = 0.028, respectively). In the SVR group, ECV fractions were significantly different between T1 and T4 and T1 and T5 (p = 0.046 and 0.022, respectively), and both FIB-4 index and APRI were significantly different between T1 and all other time points (p = 0.017 to p < 0.001 and p = 0.001 to p < 0.001, respectively). Conclusion: After DAA, ECV fraction decreased slowly, suggesting an improvement in hepatic fibrosis, while serological liver fibrosis markers decreased immediately, probably due to improvement in hepatic inflammation. Advances in knowledge: ECV fraction has the potential to be a non-invasive biomarker for the assessment of liver fibrosis after direct-acting antiviral therapy.

Objectives The objective of this study was to develop and validate a state-of-the-art, deep learning (DL)-based model for detecting breast cancers on mammography. Methods Mammograms in a hospital development dataset, a hospital test dataset, and a clinic test dataset were retrospectively collected from January 2006 through December 2017 in Osaka City University Hospital and Medcity21 Clinic. The hospital development dataset and a publicly available digital database for screening mammography (DDSM) dataset were used to train and to validate the RetinaNet, one type of DL-based model, with five-fold cross-validation. The model’s sensitivity and mean false positive indications per image (mFPI) and partial area under the curve (AUC) with 1.0 mFPI for both test datasets were externally assessed with the test datasets. Results The hospital development dataset, hospital test dataset, clinic test dataset, and DDSM development dataset included a total of 3179 images (1448 malignant images), 491 images (225 malignant images), 2821 images (37 malignant images), and 1457 malignant images, respectively. The proposed model detected all cancers with a 0.45–0.47 mFPI and had partial AUCs of 0.93 in both test datasets. Conclusions The DL-based model developed for this study was able to detect all breast cancers with a very low mFPI. Our DL-based model achieved the highest performance to date, which might lead to improved diagnosis for breast cancer.

The systemic inflammatory response is attracting increasing attention as a predictive biomarker for oncological outcome in patients with colorectal cancer. This study is aimed at verifying if the lymphocyte–C-reactive protein (CRP) ratio (LCR) could be used as a predictor of oncological outcome in patients with rectal cancer (RC) receiving preoperative chemoradiotherapy (CRT). We analyzed data for 86 patients with RC who received preoperative CRT followed by total mesorectal excision at our institution. A ratio of 6000 was used as the cut-off value for LCR for further analysis. The post-CRT LCR was significantly lower than the pre-CRT LCR in patients with RC. Although post-CRT LCR status was not significantly correlated with overall survival (OS), low pre-CRT LCR was significantly associated with shorter recurrence-free survival (RFS: p = 0.02) and OS (p = 0.017) in this population and was an independent prognostic factor for both RFS and OS (hazard ratio (HR) 3.19, 95% confidence interval (CI) 1.33–7.66, p = 0.009; HR 2.83, 95%CI 1.14–7.01, p = 0.025, respectively). Furthermore, low pre-CRT LCR was a stronger indicator of early recurrence (p = 0.001) and poor prognosis (p = 0.025) in RC patients without pathological lymph node metastasis compared with patients with pathological lymph node metastasis, and prognostic potential of pre-CRT LCR was clearly revealed especially RC patients receiving long-course CRT. Assessment of pretreatment LCR status might aid decision-making regarding postoperative treatment strategies in patients with RC receiving CRT followed by potentially curative resection.

Nitric oxide (NO) deficiency is known to play a role in renal ischaemia/reperfusion injury; therefore, kidney-targeting NO donor is expected to prevent renal ischaemia/reperfusion injury. We therefore developed an S-nitrosylated L-serine-modified polyamidoamine dendrimer (SNO-Ser-PAMAM), in which multiple S-nitrosothiols (NO donors) were covalently bound to L-serine-modified dendrimer, as a kidney-targeting NO donor. In the pharmacokinetic study, approximately 76% of

Transdermal drug delivery is an attractive route for administration of drugs, and it offers several advantages such as painless administration. To accurately predict the rate of human skin permeation for new transdermal drug formulations, we developed a novel assessment system using induced pluripotent stem cells (iPSCs). Skin was generated from iPSC-derived keratinocytes and fibroblasts. In the histological and immunohistochemical examination, cellular markers (keratin 14 and keratin 10) for the epidermal basal and suprabasal layers were clearly detected within the multilayer structures produced in the human iPSC-based three-dimensional skin model. The results from our permeation study indicate that an initial lag time exists during permeation of 5(6)-carboxyfluorescein and fluorescein isothiocyanate dextran 4000. Furthermore, the permeation for these model drugs in human iPSC-based skin was inversely proportional to the molecular weight of the drugs. These results of the present iPSC-based skin are useful basic information as a first step for developing a new assessment system to predict the efficacy of drug permeation in human skin by using iPSC-based skin.

BACKGROUND AND AIM Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains the most common and serious adverse event associated with ERCP. Risk factors for PEP have been described in various reports. However, risk factors have not been quantified to date. The aim of this study was to investigate the risk factors for PEP by quantification of pancreatic volume using pre-ERCP images. METHODS Overall, 800 patients were recruited from April 2012 to February 2015 for this study. There were 168 patients who satisfied the inclusion criteria. Measurement of pancreatic volume was achieved using the volume analyzer SYNAPSE VINCENT in all cases and was used to evaluate the risk factors for PEP. RESULTS According to the criteria established by the consensus guidelines (Cotton classification), 17 patients (10.1%) were classified as having mild disease, 4 (2.4%) as having moderate disease, and 5 (3.0%) as having severe disease. Multivariate model analysis showed that a large pancreatic volume was a significant risk factor for PEP (odds ratio [OR] 1.10, 95% confidence interval [CI] 1.06-1.13; P

Objective Balloon-occluded retrograde transvenous obliteration (B-RTO) for gastric varices (GV) is associated with drawbacks including a postoperative increase in portal pressure and the risk of subsequent worsening of esophageal varices (EV). Selective B-RTO that embolizes only the varices may have the potential to minimize such risks. The aim of this study is to retrospectively compare the postoperative course of patients after selective B-RTO (Group S) and conventional B-RTO (Group B). Methods One hundred four patients treated from January 2007 to April 2012 were classified into Groups S (n=5) and B (n=99). In the univariate analysis, the volume of 5% ethanolamine oleate iopamiodol (EOI) administered at baseline and the GV blood flow on endoscopic ultrasound after B-RTO were considered as covariates. The rates of GV recurrence and EV aggravation was also compared between Groups B and S. Results In Group S, the volume of 5% EOI was significantly lower (Group S vs. Group B: 14.6±5.5 vs. 28.5±16.4 mL; p=0.0012) and the rate of EV aggravation was lower in comparison to Group B (p=0.045). However, in Group S, the rate of complete eradication of GV blood flow was significantly lower (Group S vs. Group B: 0% vs. 89.9%; p

Objective Therapeutic predictors derived from the venous pressure before therapy have not been identified for Budd-Chiari syndrome (BCS). The aim of this study was to determine whether or not measuring the distal pressure or pressure gradient was useful for predicting treatment efficacy in BCS. Methods We retrospectively analyzed seven consecutive patients diagnosed with symptomatic BCS at our hospital between 2008 and 2017. Distal and proximal venous pressures at occlusion sites of BCS were measured before treatment in all cases. The pressure gradient was defined as the difference between distal and proximal venous pressures. A receiver operating characteristics (ROC) analysis was performed for venous pressures. Results Percutaneous old balloon angioplasty (POBA) was performed in seven cases, with technical success achieved in all cases (100%). No complications were encountered. The median primary patency was 574 (interquartile range, 439.5-1,056.5) days. The 1-year primary patency rate was 71.73%. Six cases (85.7%) showed resolution of symptoms, representing clinical success. The ROC analysis revealed a high distal pressure (area under the ROC curve = 0.83, cut-off=12 mmHg) as a predictor of treatment efficacy of POBA for symptomatic BCS. In addition, the pressure gradient was considered significant from a clinical perspective, because the 6 successful cases with resolution of symptoms showed a large pressure gradient (range, 8-21 mmHg) before treatment, whereas the failed case showed a relatively small pressure gradient (7 mmHg). Conclusion High distal pressure and a large pressure gradient might predict the treatment efficacy of balloon angioplasty for symptomatic BCS.

Background Sarcopenia frequently occurs in metastatic cancer patients. Emerging evidence has revealed that various secretory products from metastatic tumours can influence host organs and promote sarcopenia in patients with malignancies. Furthermore, the biological functions of microRNAs in cell‐to‐cell communication by incorporating into neighbouring or distal cells, which have been gradually elucidated in various diseases, including sarcopenia, have been elucidated. Methods We evaluated psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) using pre‐operative computed tomography imaging in 183 colorectal cancer (CRC) patients. miR‐203 expression levels in CRC tissues and pre‐operative serum were evaluated using quantitative polymerase chain reaction. Functional analysis of miR‐203 overexpression was investigated in human skeletal muscle cells (SkMCs), and cells were analysed for proliferation and apoptosis. Expressions of several putative miR‐203 target genes (CASP3, CASP10, BIRC5, BMI1, BIRC2, and BIRC3) in SKMCs were validated. Results A total of 183 patients (108 men and 75 women) were included. The median age of enrolled patients at diagnosis was 68.0 years (range 35–89 years). High IMAC status significantly correlated with female gender (P = 0.004) and older age (P = 0.0003); however, no other clinicopathological factors correlated with IMAC status in CRC patients. In contrast, decreased PMI significantly correlated with female gender (P = 0.006) and all well‐established disease development factors, including advanced T stage (P = 0.035), presence of venous invasion (P = 0.034), lymphovascular invasion (P = 0.012), lymph node (P = 0.001), distant metastasis (P = 0.002), and advanced Union for International Cancer Control tumour–node–metastasis stage classification (P = 0.0004). Although both high IMAC status and low PMI status significantly correlated with poor overall survival (IMAC: P = 0.0002; PMI: P

Breast cancer resistance protein transporter (ABCG2/BCRP) is highly expressed on the intestinal epithelial membrane and has a significant impact on the oral absorption of topotecan. In this study, we examined 6 pharmaceutical excipients including BL-9EX, Brij97, Cremophor EL, Labrasol, Pluronic F68, and Tween 20 for their BCRP inhibitory effects. A bidirectional transport study using Caco-2 cells demonstrated that Tween 20 and Cremophor EL significantly increased the absorptive transport of topotecan, while simultaneously decreasing secretory transport. Interestingly, Labrasol selectively increased absorptive transport, whereas Pluronic F68 selectively decreased the secretory transport, of topotecan. Further investigation using an in situ closed loop experiment showed that 0.05% (w/v) Tween 20 and Cremophor EL significantly increased the intestinal absorption of topotecan in rats. An LDH assay demonstrated that 0.05% (w/v) Tween 20 and Cremophor EL did not cause significant damage to intestinal epithelial membranes. Furthermore, we examined the absorption-enhancing mechanisms of these excipients and found that Cremophor EL, Tween 20, and Labrasol increased the membrane fluidity of the inner lipid bilayers of the intestine. Therefore, this might be one of the most important mechanisms for inhibition of BCRP function by these excipients in the intestine.

Diffusion-weighted imaging (DWI), a key component in multiparametric MRI (mpMRI), is useful for tumor detection and localization in clinically significant prostate cancer (csPCa). The Prostate Imaging Reporting and Data System versions 2 and 2.1 (PI-RADS v2 and PI-RADS v2.1) emphasize the role of DWI in determining PIRADS Assessment Category in each of the transition and peripheral zones. In addition, several recent studies have demonstrated comparable performance of abbreviated biparametric MRI (bpMRI), which incorporates only T2-weighted imaging and DWI, compared with mpMRI with dynamic contrast-enhanced MRI. Therefore, further optimization of DWI is essential to achieve clinical application of bpMRI for efficient detection of csPC in patients with elevated PSA levels. Although DWI acquisition is routinely performed using single-shot echo-planar imaging, this method suffers from such as susceptibility artifact and anatomic distortion, which remain to be solved. In this review article, we will outline existing problems in standard DWI using the single-shot echo-planar imaging sequence; discuss solutions that employ newly developed imaging techniques, state-of-the-art technologies, and sequences in DWI; and evaluate the current status of quantitative DWI for assessment of tumor aggressiveness in PC.

Chylothorax is a rare clinical sign in patients with diffuse large B-cell lymphoma (DLBCL), which is often challenging to manage and has a poor prognosis. We report the case of a 59-year-old woman who presented with right pleural effusion at the time of DLBCL diagnosis. Lymphadenopathy rapidly improved in response to chemotherapy. However, the pleural effusion progressed and was identified as chylothorax by thoracentesis. Because attempts to manage the condition with fasting and central venous nutrition were unsuccessful, we performed ultrasound-guided intranodal lipiodol lymphangiography from the inguinal lymph node. Although leak sites were not detected, the pleural effusion markedly improved on the day after the examination and resolved after 2 months. Lymphangiography is a minimally invasive examination with few complications. It contributes not only to the identification of leak sites but also to the improvement and resolution of chylothorax. Therefore, lymphangiography should be considered for refractory chylothorax that is unresponsive to chemotherapy or nutritional management.

Significant shape changes in the human facial skeleton occur in the early prenatal period, and understanding this process is critical for studying a myriad of congenital facial anomalies. However, quantifying and visualizing human fetal facial growth has been challenging. Here, we applied quantitative geometric morphometrics (GM) to high-resolution magnetic resonance images of human embryo and fetuses, to comprehensively analyze facial growth. We utilized non-linear growth estimation and GM methods to assess integrated epigenetic growth between masticatory muscles and associated bones. Our results show that the growth trajectory of the human face in the early prenatal period follows a curved line with three flexion points. Significant antero-posterior development occurs early, resulting in a shift from a mandibular prognathic to relatively orthognathic appearance, followed by expansion in the lateral direction. Furthermore, during this time, the development of the zygoma and the mandibular ramus is closely integrated with the masseter muscle.

Dieulafoy lesions are rare vascular malformations of the gastrointestinal tract; however, they can lead to fatal vascular bleeding. Immunoglobulin G4-related disease (IgG4-RD) is a rare systemic fibroinflammatory disease involving multiple organs, including the vasculature. To date, no autopsy reports of Dieulafoy lesions with IgG4-RD have been described in the literature. A 48-year-old man was found dead in his home with hematochezia. Postmortem computed tomography revealed high-density gastric contents and an enlarged iso-density area in the pancreas, indicating gastric hemorrhage and mass-forming lesions. Macroscopic and histological examinations revealed an ulcer of the body of the stomach with a large amount of hemorrhage from the enlarged artery in the submucosal layer, confirming the rupture of the Dieulafoy lesion. Moreover, lymphocyte infiltrations with increased IgG4 positive cells were found in the pancreas, thyroid gland, and arteries in non-ulcer regions of the stomach, suggesting IgG4-RD. Serum biochemical analysis showed elevated levels of inflammatory mediators, such as IgE, soluble-interleukin-2 receptor, and C-reactive protein. These findings suggest that systemic inflammation caused by IgG4-RD could, at least in part, contribute to the development of Dieulafoy lesions and fatal rupture of the lesion. This case report highlights the importance of autopsy research focusing on Dieulafoy lesions and IgG4-RD to promote awareness and a better understanding of the relationships between these treatable diseases to establish earlier and effective interventional strategies for better patient outcomes.

To develop a deep learning (DL) model to generate synthetic, 2-dimensional subtraction angiograms free of artifacts from native abdominal angiograms.In this retrospective study, 2-dimensional digital subtraction angiography (2D-DSA) images and native angiograms were consecutively collected from July 2019 to March 2020. Images were divided into motion-free (training, validation, and motion-free test datasets) and motion-artifact (motion-artifact test dataset) sets. A total of 3,185, 393, 383, and 345 images from 87 patients (mean age, 71 years ± 10; 64 men and 23 women) were included in the training, validation, motion-free, and motion-artifact test datasets, respectively. Native angiograms and 2D-DSA image pairs were used to train and validate an image-to-image translation model to generate synthetic DL-based subtraction angiography (DLSA) images. DLSA images were quantitatively evaluated by the peak signal-to-noise ratio (PSNR) and structural similarity (SSIM) using the motion-free dataset and were qualitatively evaluated via visual assessments by radiologists with a numerical rating scale using the motion-artifact dataset.The DLSA images showed a mean PSNR (± standard deviation) of 43.05 dB ± 3.65 and mean SSIM of 0.98 ± 0.01, indicating high agreement with the original 2D-DSA images in the motion-free dataset. Qualitative visual evaluation by radiologists of the motion-artifact dataset showed that DLSA images contained fewer motion artifacts than 2D-DSA images. Additionally, DLSA images scored similar to or higher than 2D-DSA images for vascular visualization and clinical usefulness.The developed DL model generated synthetic, motion-free subtraction images from abdominal angiograms with similar imaging characteristics to 2D-DSA images.

Bronchiolitis obliterans syndrome (BOS) remains one of the most devastating manifestations of chronic graft-versus-host disease in hematopoietic cell transplantation (HCT). Recent findings of BOS after lung transplantation indicate that donor (lung)-derived lung-resident macrophages contribute to BOS, suggesting that differences in the origin of immune cells and localized antigen-presenting cells cause the onset of BOS. We identified the phenotype and origin of infiltrating macrophages using immunohistochemistry and fluorescence in situ hybridization in eight sex-mismatched HCT recipients who underwent lung transplantation for BOS after HCT. Most of the infiltrating macrophages appeared to be derived from donor (hematopoietic) cells in patients who developed BOS following HCT. Macrophages observed in the early-stage region of BOS were positive for cluster of differentiation (CD)68 and inducible nitric oxide synthase (iNOS) and negative for CD163 and CD206, suggesting an M1 phenotype. In the late-stage region, macrophages were negative for CD68 and iNOS in all patients, but also positive for CD163 and CD206 in some patients. Donor-derived M1-macrophages may be involved in the pathogenesis of the early-stage region of BOS. In addition, some macrophages in the late-stage region showed M2 polarization that might be involved in fibrosis.

Aim The clinical significance of the geriatric nutritional risk index (GNRI) in locally advanced rectal cancer (LARC) patients undergoing preoperative chemoradiotherapy (CRT) followed by curative surgery has not been comprehensively evaluated. Methods This retrospective study enrolled 93 LARC patients diagnosed with clinical lymph node metastasis. The GNRI formula was as follows: 1.489 × albumin (g/l) + 41.7 × current weight/ideal weight. Patients were categorized as GNRI low (GNRI 104.25) according to the receiver operating characteristic (ROC) curve for survival analysis. The impact of GNRI status on the prognostic outcomes of curative surgery for LARC was examined. Results There were 55 (59.14%) and 38 (40.86%) patients in the GNRI high and low groups, respectively. Of the investigated demographic factors, age, pathological tumor invasion, and presence of recurrence were significantly associated with the GNRI value. In Kaplan–Meier analysis, overall survival (OS) and disease-free survival (DFS) were significantly shorter in the GNRI low group (OS: p = 0.00020, DFS: p = 0.0044, log-rank test). Multivariate analysis using a Cox proportional hazards model showed that a low GNRI was an independent risk factor for poor OS (hazard ratio (HR) = 3.22; 95% confidence interval (CI), 1.37–8.23; p = 0.0068) and DFS (HR = 2.32; 95%CI = 1.15–4.79; p = 0.018). Although use of adjuvant therapy has no impact on prognosis (OS: p = 0.26, DFS: p = 0.29), low GNRI showed shorter OS and DFS in patients with pathological lymph node metastasis [ypN(+)] (OS: p = 0.033, DFS: p = 0.032, log-rank test). Conclusions GNRI is a useful marker for LARC patients diagnosed with clinical lymph node metastasis and treated by preoperative CRT followed by curative surgery. GNRI is a useful tool to identify high risk of recurrence for improving the survival in LARC patients.

To establish a system for assessing drug permeation and irritation of the skin, the permeation of benzoic acid and isosorbide dinitrate, which are listed in the Pharmacopoeia, and the chemical irritation were evaluated using skin generated from human induced pluripotent stem cells (iPSCs). Multilayer structures and cellular markers (keratin 14 and 10, which are in basal and suprabasal epidermal layers) were clearly detected in our iPSC-based skin. Transepidermal water loss (TEWL) decreased after iPSC-derived keratinocytes were cultured on collagen gels from human primary fibroblasts. These results indicate that the barrier function was partly increased by formation of the living epidermis. The cumulative amount of benzoic acid and isosorbide dinitrate across human iPSC-based skin gradually increased after an initial lag time. Moreover, the irritancy of various chemicals (non-irritants: ultrapure water, allyl phenoxy-acetate, isopropanol, and hexyl salicylate and irritants: 5% sodium dodecyl sulfate (SDS), heptanal, potassium hydroxide (5% aq.) and cyclamen aldehyde) to iPSC-based skin was almost met the irritation criteria of the Organisation for Economic Co-operation and Development (OECD) guideline. The results of our iPSC-based skin evaluation provide useful basic information for developing an assessment system to predict the permeation and safety of new transdermal drugs in human skin.

Objective Patients who undergo Fontan surgery for complex cardiac anomalies are prone to developing liver and gastrointestinal complications. In particular, gastroesophageal varices (GEVs) can occur, but their prevalence is unknown. We aimed to elucidate the occurrence of GEVs and the predicting parameters of GEVs in these patients. Materials and methods Twenty-seven patients (median age, 14.8 years; median time since surgery, 12.9 years) who had undergone the Fontan surgery and were examined by abdominal dynamic computed tomography (CT) for the routine follow-up were included in the study. Radiological findings including GEVs and extraintestinal complications were retrospectively evaluated by experienced radiologists in a blinded manner. Relationships between blood-biochemical and demographic parameters and the presence of GEVs were statistically analyzed. Results Dynamic CT revealed gastric varices (n = 3, 11.1%), esophageal varices (n = 1, 3.7%), and gastrorenal shunts (n = 5, 18.5%). All patients with gastric varices had gastrorenal shunts. All gastric varices were endoscopically confirmed as being isolated and enlarged, with indications for preventive interventional therapy. A platelet count lower than 119 × 109 /L was identified as a predictor of GEV (area under the receiver operating curve, 0.946; sensitivity, 100%; and specificity, 87%). Conclusions GEVs are important complications that should not be ignored in patients who have undergone a Fontan procedure. Platelet counts lower than 119 × 109 /L may help to prompt patient screening by using abdominal dynamic CT to identify GEVs and their draining collateral veins in these patients.

BACKGROUND The advanced lung cancer inflammation index is considered a useful prognostic biomarker of clinical outcomes in patients with malignancies. However, the prognostic value of the advanced lung cancer index in patients with colorectal cancer who underwent surgical resection remains unclear. OBJECTIVE In this study, we evaluated the prognostic value of the advanced lung cancer index in patients with colorectal cancer. DESIGN Prospectively obtained data of patients with colorectal cancer were retrospectively evaluated to clarify the clinical relevance of the advanced lung cancer index. SETTINGS We conducted this study at a single expert center. PATIENTS We enrolled 298 patients with colorectal cancer who underwent surgical resection in this retrospective study. MAIN OUTCOME MEASURES The primary outcome was the clinical relevance of the advanced lung cancer index in patients with rectal cancer. RESULTS Low status of advanced lung cancer index was significantly correlated with undifferentiated histology (p = 0.004), T stage progression (p < 0.001), R1/R2 resection for primary surgery (p = 0.004), and distant metastasis (p < 0.001). Multivariate analysis showed that low advanced lung cancer index status was an independent prognostic factor for both overall survival (HR = 3.21 (95% CI, 1.97-5.19); p < 0.001) and disease-free survival (HR = 2.13 (95% CI, 1.23-3.63); p = 0.008) in patients with colorectal cancer. Furthermore, the clinical burden of the advanced lung cancer index was consistent between sexes, and its prognostic value was verified in patients with clinically relevant stage III colorectal cancer. LIMITATIONS The present study had several limitations, including retrospective observation and a small sample size of Japanese patients from a single institution. CONCLUSIONS The advanced lung cancer index could be a useful prognostic indicator of clinical outcomes in patients who underwent surgical resection for colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B267. EL INDICE AVANZADO DE INFLAMACION DEL CANCER DE PULMON, PREDICE LOS RESULTADOS DE LOS PACIENTES CON CANCER COLORRECTAL DESPUES DE LA RESECCION QUIRURGICA: El indice avanzado de inflamacion del cancer de pulmon, es considerado como un util biomarcador pronostico, en los resultados clinicos de pacientes con neoplasias malignas. Sin embargo, aun no esta claro el valor pronostico del indice avanzado de cancer de pulmon, en pacientes con cancer colorrectal sometidos a reseccion quirurgica.Evaluar el valor pronostico del indice avanzado del cancer de pulmon, en pacientes con cancer colorrectal.Los datos obtenidos prospectivamente de pacientes con cancer colorrectal, fueron evaluados retrospectivamente, para aclarar la relevancia clinica del indice avanzado del cancer de pulmonEstudio realizado en un solo centro experto.Estudio retrospectivo, incluyendo 298 pacientes con cancer colorrectal, sometidos a reseccion quirurgica.El resultado primario fue la relevancia clinica del indice avanzado de cancer de pulmon, en pacientes con cancer rectal.Un indice avanzado de cancer de pulmon bajo, se correlaciono significativamente con la histologia indiferenciada (p = 0.004), la progresion de la etapa T (p

The morphologic changes in the compensated stage of liver cirrhosis (cLC) are not diffuse atrophic changes. With cLC lobar or segmental changes combined with atrophy of the right lobe and medial segment together with hypertrophy of the caudate lobe and lateral segment are commonly seen. The purpose of this study was to evaluate the morphologic changes in hepatitis virus-related liver cirrhosis in relationship to haemodynamics of the portal vein on dynamic contrast-enhanced computed tomography (DCE-CT) METHODS: This study included 72 patients, 46 with hepatitis virus-related cirrhosis and 26 with a normally functioning liver, who underwent DCE-CT. In cirrhosis patients, the morphologic change index (MCI) of the liver was calculated and categorised into two groups, high-MCI (MCI ≥ 0.4) (n = 21) and low-MCI (MCI 0.4) (n = 25). Cross-sectional areas of the main, right and left portal veins and the intra-portal distribution from splenic venous flow were evaluated for their relationships with the MCI and compared among three groups (normal-control, low MCI and high MCI).There was a significant difference in the cross-sectional area of the left portal vein between the high-MCI group and the low-MCI group (p = 0.013) and the control group (p = 0.008). A significant correlation was identified between the cross-sectional area of the left portal vein and the MCI (r = 0.508, p 0.001).Cross-sectional area of the left portal vein may be a factor related to morphologic changes in hepatitis virus-related liver cirrhosis and could be a possible index of the left portal venous flow volume.This study may be useful for predicting the degree of hepatic morphologic changes and the condition of cirrhosis in association with regional hepatic morphologic changes.