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We have developed ethanol therapy for infectious atheroma based on the experience of two cases in which ethanol was injected into the liver cyst and the cyst shrank. For 64 infectious atheromas, atheroma contents were excreted and the cyst wall was contacted with 76% ethanol gauze for 5 minutes. Postoperatively, the cyst was washed daily as an open drainage. All cases were cured 10 days postoperatively, and no side effects. Postoperative follow-up study results in 36 cases showed no recurrence in an average of 5 years. Pathological examination revealed koilocytosis in 14 of 25 cases (56.0%), which is considered to be an indirect finding of viral infection. The changes in human papillomavirus (HPV 16) before and after ethanol therapy in 25 cases using the Bi-Digital O- ring Test (BDORT) decreased significantly from 1026.0 ng (BDORT units) preoperatively to 1.6ng (BDORT units) postoperatively. In also 12 cases follow- up study without microscopy HPV 16 same decreased from 1064.2ng to 1.2ng (BDORT unit) using BDORT with atheroma photographs. In total, HPV 16 could be demonstrated in 37 of 64 cases (57.8%) using BDORT. Temporal changes of HPV 16 used for BDORT in 7 cases after contact with ethanol were inactivated after 3 minutes 30 seconds. The involvement of HPV 16 is suggested as the cause of atheroma. It is speculated that ethanol inactivated HPV 16 of atheroma, which stopped the turnover of the squamous epithelium and prevented recurrence. Ethanol therapy for infectious atheroma is useful as an original new one-stage surgery because it is a simple procedure and has no side effects or recurrence.

Background and Aims Kupffer-phase imaging visualized by perfluorobutane (Sonazoid) distribution into normal liver tissues upon phagocytosis by Kupffer cells potentially aids in improving detection of liver metastasis compared with fundamental B-mode EUS (FB-EUS). However, the diagnostic performance of Kupffer-phase imaging in contrast-enhanced harmonic EUS (CH-EUS) remains unclear. Hence, this study aimed to evaluate the usefulness of CH-EUS-based Kupffer-phase imaging for diagnosing liver metastasis from pancreatic cancer. Methods We retrospectively analyzed consecutive patients with pancreatic cancer who underwent contrast-enhanced CT (CE-CT) and FB-EUS, followed by CH-EUS, from 2011 to 2017. The diagnostic ability of CH-EUS against that of CE-CT and FB-EUS for metastasis in the left liver lobe was compared. Subsequently, the influences of CH-EUS on the determination of clinical stage and patient management for pancreatic cancer were assessed. Results We enrolled 426 patients with pancreatic cancer. Metastasis in the left liver lobe was present in 27.2% of patients. The diagnostic accuracy of CE-CT, FB-EUS, and CH-EUS was 90.6%, 93.4%, and 98.4%, respectively. The sensitivity and diagnostic accuracy of CH-EUS for metastasis in the left liver lobe were significantly higher than those of FB-EUS or CE-CT. The sensitivity of CH-EUS for detecting small liver metastasis ( Conclusions CH-EUS-based Kupffer-phase imaging increased the detectability of metastasis in the left liver lobe. This technique could be a reliable pretreatment imaging modality for clinical decision-making in patients with pancreatic cancer.

Treacher Collins syndrome (TCS) is a heterogenous malformation syndrome characterized by a distinct facial appearance including downslanting palpebral fissures, malar hypoplasia, conductive hearing loss, and mandibular hypoplasia. Recently, a new causative gene, POLR1B, encoding DNA-directed RNA polymerase I subunit RPA2, was identified as a fourth type of TCS (TCS4). We describe another patient with TCS4 caused by a recurrent POLR1B variant, c.3007C>T; p.Arg1003Cys. Including our patient, all 4 patients with p.(Arg1003Cys) had atresia of the external auditory canal and microtia. All of the reported pathogenic variants in POLR1B were clustered at only 2 residues. Our patient highlights the genotype-phenotype correlation in TCS4 associated with POLR1B.

Background In recent years, locomotive syndrome, which is a condition requiring nursing care due to musculoskeletal disease, has been reported, and interest in knee osteoarthritis has been increasing. Several studies have reported the physical factors influencing the relationship between knee osteoarthritis and health-related quality of life (HRQOL), but there have been no reports verifying the changes over time in the relationship between psychosocial factors and HRQOL. This study aimed to investigate the influence of psychosocial factors on HRQOL in elderly patients with knee osteoarthritis. Methods Evaluations were conducted at four time points: before exercise therapy intervention, 1 month into intervention, 3 months into intervention, and 1 month after completion of intervention. The items investigated were (1) Japanese Orthopedic Association (JOA) score, (2) Kellgren-Lawrence (K-L) grading system, (3) Fall Efficacy Scale (FES), (4) Frenchay Activities Index (FAI), (5) Geriatric Depression Scale (GDS), and (6) Short Form-8 (SF-8). Results No significant differences were seen between each time point of exercise therapy intervention in depression and HRQOL scale but a significant improvement was seen in instrumental ADL and fear of falling at 3 months into intervention. On multiple regression analysis with SF-8 subscales, fear of falling and degree of depression were determined as significant factors affecting physical and mental summary scores. Conclusion Elderly patients with knee osteoarthritis require not only intervention for knee function, but also psychological intervention to address decreased activity and depression to improve their HRQOL.

Objective The aim of the study was to characterize magnetic resonance imaging findings in patients with recurrent ovarian adult granulosa cell tumors (AGCTs). Methods Clinical and magnetic resonance imaging manifestations of recurrent AGCTs were evaluated in 11 patients. Results Initial recurrences of AGCT were diagnosed between 13 months and 30 years (mean, 11.3 years). Recurrent tumors were located in the pelvic peritoneum, the abdominal peritoneum, the retroperitoneum, and bone. The number of recurrent tumors varied from 1 to 5. Tumors varied in morphology and all margins were well circumscribed. The internal structures noted were as follows: multilocular cystic and solid and cystic. Furthermore, internal hemorrhage and sponge-like multicystic components were identified. Conclusions Ovarian AGCTs recurred in the pelvic peritoneum, abdominal peritoneum, and the retroperitoneal lymph nodes. Large recurrent AGCTs were commonly well circumscribed, round or lobulated, and multilocular cystic or solid and cystic. Moreover, they frequently included internal hemorrhage and sponge-like multicystic components.

Kabuki syndrome is characterized by a variable degree of intellectual disability, characteristic facial features, and complications in various organs. Many variants have been identified in two causative genes, that is, lysine methyltransferase 2D (KMT2D) and lysine demethylase 6A (KDM6A). In this study, we present the results of genetic screening of 100 patients with a suspected diagnosis of Kabuki syndrome in our center from July 2010 to June 2018. We identified 76 variants (43 novel) in KMT2D and 4 variants (3 novel) in KDM6A as pathogenic or likely pathogenic. Rare variants included a deep splicing variant (c.14000-8C>G) confirmed by RNA sequencing and an 18% mosaicism level for a KMT2D mutation. We also characterized a case with a blended phenotype consisting of Kabuki syndrome, osteogenesis imperfecta, and 16p13.11 microdeletion. We summarized the clinical phenotypes of 44 patients including a patient who developed cervical cancer of unknown origin at 16 years of age. This study presents important details of patients with Kabuki syndrome including rare clinical cases and expands our genetic understanding of this syndrome, which will help clinicians and researchers better manage and understand patients with Kabuki syndrome they may encounter.

BackgroundVariants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear.MethodsWe examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.ResultsPathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.ConclusionsPrenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

To evaluate the performance of a deep learning-based computer-aided diagnosis (CAD) system at detecting pulmonary nodules on CT by comparing radiologists’ readings with and without CAD. A total of 120 chest CT images were randomly selected from patients with suspected lung cancer. The gold standard of nodules ≥ 3 mm was established by a panel of three expert radiologists. Two less experienced radiologists read the images without and afterward with CAD system. Their reading times were recorded. The radiologists’ sensitivity increased from 20.9% to 38.0% with the introduction of CAD. The positive predictive value (PPV) decreased from 70.5% to 61.8%, and the F1-score increased from 32.2% to 47.0%. The sensitivity significantly increased from 13.7% to 32.4% for small nodules (3–6 mm) and from 33.3% to 47.6% for medium nodules (6–10 mm). CAD alone showed a sensitivity of 70.3%, a PPV of 57.9%, and an F1-score of 63.5%. Reading time decreased by 11.3% with the use of CAD. CAD improved the less experienced radiologists’ sensitivity in detecting pulmonary nodules of all sizes, especially including a significant improvement in the detection of clinically important-sized medium nodules (6–10 mm) as well as small nodules (3–6 mm) and reduced their reading time.

Objective To report clinical features of bone metastases (BM) from head and neck squamous cell carcinoma (HNSCC). Methods Among 772 patients with HNSCC diagnosed at our hospital over 9 years, 30 patients (3.9%) had clinical evidence of BM (24 men and 6 women; mean age: 63 years). We assessed the time interval from the primary diagnosis to BM development, symptoms attributable to BM, presence of distant metastases to other organs, number of BM, sites of BM, morphologic changes on computed tomography (CT) images, treatment for BM, and overall survival (OS). Results BM at the initial stage were found in 9 patients with HNSCC (30%), and in 21 patients (70%) with HNSCC during the course of the disease. In the later patients, the median time interval from the primary diagnosis was 11.5 months. Nineteen patients (63%) did not have BM-related symptoms, 6 (20%) had pain, 3 (10%) had neurologic symptoms resulting from vertebral or skull metastases, and 2 (7%) had hypercalcemia. Seventeen patients (57%) showed bone-exclusive metastases, and 13 (43%) had distant metastases in other organs. Eleven patients (37%) had monostotic metastases (solitary BM), and 19 patients (63%) had polyostotic metastases (multiple BM). When combined, 9 patients (30%) showed bone-exclusive and monostotic metastases. The most commonly affected site was the thoracolumbar spine, accounting for 34% of total BM, followed by the pelvis (24%), shoulder and thorax (21%), and the extremities (17%). Notably, metastases to bones above the clavicle (craniofacial bones and cervical spine) accounted for only 3% of all bone lesions. CT images showed variable morphologic patterns with osteolytic type in 17 patients (57%), intertrabecular in 7 (23%), osteoblastic in 4 (13%), and mixed in 2 (7%). Systematic chemotherapy for BM was performed in 19 patients and radiotherapy in 18. The median survival time for patients with bone-exclusive and monostotic metastases was significantly longer than that for patients with multi-organ metastases or polyostotic metastases at 18.2 months vs. 5.7 months (p = 0.02). Neither chemotherapy nor radiotherapy extended OS. Conclusion Thirty percent of BM cases from HNSCC showed bone-exclusive and monostotic metastases. These patients tended to show a more favorable prognosis than patients with multi-organ metastases or polyostotic metastases.

Background: Pancreatic cancer (PC) exhibits extremely rapid growth, however, it remains largely unknown whether the early stages of PC also exhibit rapid growth speed equivalent to advanced PC. This study aimed to investigate the natural history of early PCs through retrospectively assessing pre-diagnostic images. Methods: We examined the data of nine patients, including three patients with carcinoma in situ (CIS), who had undergone magnetic resonance cholangiopancreatography (MRCP) to detect solitary main pancreatic duct (MPD) stenosis &gt, 1 year before definitive PC diagnosis. We retrospectively analyzed the time to diagnosis and first-time tumor detection from the estimated time point of first-time MPD stenosis detection without tumor lesion. Results: The median tumor size at diagnosis and the first-time tumor detection size were 14 and 7.5 mm, respectively. The median time to diagnosis and first-time tumor detection were 26 and 49 months, respectively. Conclusions: No studies have investigated the PC history, especially that of early PCs, including CIS, based on the initial detection of MPD stenosis using MRCP. Assessment of a small number of patients showed that the time to progression can take several years in the early PC stages. Understanding this natural history is very important in the clinical setting.

During the last three decades, Delhi has witnessed extensive and rapid urban expansion in all directions, especially in the East South East zone. The total built-up area has risen dramatically, from 195.3 sq. km to 435.1 sq. km, during 1989–2020, which has led to habitat fragmentation, deforestation, and difficulties in running urban utility services effectively in the new extensions. This research aimed to simulate urban expansion in Delhi based on various driving factors using a logistic regression model. The recent urban expansion of Delhi was mapped using LANDSAT images of 1989, 2000, 2010, and 2020. The urban expansion was analyzed using concentric rings to show the urban expansion intensity in each direction. Nine driving factors were analyzed to detect the influence of each factor on the urban expansion process. The results revealed that the proximity to urban areas, proximity to main roads, and proximity to medical facilities were the most significant factors in Delhi during 1989–2020, where they had the highest regression coefficients: −0.884, −0.475, and −0.377, respectively. In addition, the predicted pattern of urban expansion was chaotic, scattered, and dense on the peripheries. This pattern of urban expansion might lead to further losses of natural resources. The relative operating characteristic method was utilized to assess the accuracy of the simulation, and the resulting value of 0.96 proved the validity of the simulation. The results of this research will aid local authorities in recognizing the patterns of future expansion, thus facilitating the implementation of effective policies to achieve sustainable urban development in Delhi.

[Purpose] To examine the validity of the predictive formulas based on the angle information of the segment center of mass and moments of inertia, and to propose a joint moment estimation method. [Participants and Methods] Twenty nine young healthy adults were divided into two groups: the Creation group (20 adults) was needed to create the prediction formulas, and the Verification group (9 adults) was needed to verify the formulas. By monitoring the Creation group, the angular information from inertial motion sensors and moments of inertia of each limb were used to estimate actual ankle joint moment and knee joint moment. Thereafter, the actual joint moments was derived from the Verification group and compared to the predicted values via Pearson correlations. [Results] Good to excellent correlations were obtained between the actual joint moments of the two groups for most of the motions. [Conclusion] It is suggested that the predictive formulas created from the angle information of the segment center of mass and moments of inertia can be used for an approximate estimation of the lower limb joint moments in the sagittal plane and more clinically useful tools need to be considered in the future.

[Purpose] The purpose of this longitudinal study was to investigate the diversity in infant crawling and examine the quantitative regularity in crawling variations necessary for the acquisition of walking in infants with typical development. [Participants and Methods] Infants with no neurological or orthopedic problems participated in this study. Using Internet Protocol (IP) cameras, crawling was simultaneously filmed from six different angles. Filming was continued until the acquisition of independent walking. The crawling movement in the video was coded. We considered the number of different completed codes as the number of variations and examined the cumulative number during the filming period in each participant. [Results] Nineteen infants completed the study. The pattern of change in the cumulative number of variations with increasing age (in days) varied between cases. Although the cumulative number of crawling variations at the time of acquisition of independent walking was inconsistent, it was negatively correlated with the crawling start age (in days). [Conclusion] Diversity exists in infant crawling. Infants who start crawling at a younger age tend to express more variation, whereas infants who start crawling when older tend to express less variation.

A 24-year-old Japanese man exhibited slowly progressive gait disturbance from childhood to young adulthood. Physical and physiological examinations showed the involvement of both upper and lower motor neurons, fulfilling the diagnostic criteria for amyotrophic lateral sclerosis (ALS). Mild cognitive impairment and subclinical sensory involvement were also observed. A genetic analysis revealed novel compound heterozygous mutations, c.767C>T (p.Thr256Ile) and c.800A>G (p.Asp267Gly), in the vaccinia-related kinase 1 gene (VRK1). This is the first report of a Japanese patient with a motor neuron disease phenotype caused by VRK1 mutations. This diagnosis should be considered in atypical cases of juvenile-onset and slowly progressive types of motor neuron disease.

Arterial spin-labeling magnetic resonance perfusion imaging is a promising tool for the diagnosis of cerebral hyperperfusion syndrome after carotid endarterectomy. However, arterial spin-labeling with a single post-labeling delay has been reported to show a higher incidence of increased arterial spin-labeling signals in the bilateral hemisphere, probably due to a shortening of the arterial transit time or an arterial transit artifact caused by intravascular stagnant magnetically-labeled spin. To overcome these shortcomings, we used two post-labeling delay settings (1.0 and 1.5 s) in 8 patients who had undergone carotid endarterectomy. In addition, we created a subtraction image between the mean perfusion maps at post-labeling delays of 1.0 and 1.5 s. This also decreased arterial transit artifacts, as these appeared in nearly the same configuration in both post-labeling delay settings. In all eight cases examined, increased arterial spin-labeling signals were observed bilaterally on both dual post-labeling delay settings. Subtraction images revealed that these increased signals were attributable to arterial transit artifacts in seven cases. However, in one patient who developed clinical symptoms, the subtraction method demonstrated post-carotid endarterectomy hyperperfusion. This preliminary study demonstrates that the subtraction method might decrease arterial transit artifacts and yield a map that can better represent true perfusion, thus enabling the detection of post-carotid endarterectomy hyperperfusion.

OBJECTIVES To compare the urinary pH, recurrence-free survival (RFS), and safety of adjuvant intravesical therapy in patients with non-muscle-invasive bladder cancer (NMIBC) receiving mitomycin C (MMC) therapy and MMC + cytosine arabinoside (Ara-C) therapy. PATIENTS AND METHODS A total of 165 patients with NMIBC from six hospitals were randomly allocated to two groups: weekly instillation of MMC + Ara-C (30 mg/30 mL + 200 mg/10 mL) for 6 weeks and the same instillation schedule of MMC (30 mg/40 mL). The primary outcome was RFS, and secondary outcomes were urinary pH and toxicity in the two groups. RESULTS A total of 81 and 87 patients were randomised into the MMC and MMC + Ara-C groups, respectively. Overall, the RFS in the MMC + Ara-C group was significantly longer (P = 0.018) than that in the MMC group. A similar significant difference was detected in patients with intermediate-risk NMIBC, but not in those with high-risk NMIBC. The mean (SD) urinary pH was significantly higher in the MMC + Ara-C group than in the MMC group, at 6.56 (0.61) vs 5.78 (0.64) (P 7.0 in the MMC and MMC + Ara-C groups was 6.3% and 26.7%, respectively (P

To evaluate the efficacy and safety of transcatheter arterial embolization (TAE) for pseudoaneurysms occurring secondary to pancreatitis or because of leakage of pancreatic juice after pancreatectomy.This retrospective study included 42 consecutive patients (38 males and 4 females; mean age, 60 years; range, 33-80 years) who underwent TAE for bleeding visceral artery pseudoaneurysms between March 2004 and December 2018. The technical and clinical success rates, incidence of recurrent bleeding, complications, including pancreatitis, and overall survival after TAE were evaluated.Of the 42 enrolled patients, 23 had bleeding due to a complication of pancreatectomy and 19 had bleeding as a complication of pancreatitis. TAE with N-butyl cyanoacrylate (NBCA) or NBCA plus microcoils recurrent bleeding or inability to control bleeding was 15.8% (3 of 19) following TAE with NBCA and 17.4% (4 of 23) following TAE with coils. No clinically significant ischemic events of the pancreas or duodenum were observed in the embolized areas. Serum amylase did not increase compared with the initial levels after any of the procedures. At 30 days after TAE, 32 patients were alive.TAE has a high success rate for the management of hemorrhage, with few complications. The procedure appears to be safe and effective for pseudoaneurysms associated with either pancreatitis or pancreatectomy.

Background: We investigate the feasibility of image fusion application for ablative margin assessment in radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) and possible causes for a wrong initial evaluation of technical success through a side-by-side comparison. Methods: A total of 467 patients with 1100 HCCs who underwent RFA were reviewed retrospectively. Seventeen patients developed local tumor progressions (LTPs) (median size, 1.0 cm) despite initial judgments of successful ablation referring to contrast-enhanced images obtained in the 24 h after ablation. The ablative margins were reevaluated radiologically by overlaying fused images pre- and post-ablation. Results: The initial categorizations of the 17 LTPs had been grade A (absolutely curative) (n = 5) and grade B (relatively curative) (n = 12), however, the reevaluation altered the response categories to eight grade C (margin-zero ablation) and nine grade D (existence of residual HCC). LTP occurred in eight patients re-graded as C within 4 to 30.3 months (median, 14.3) and in nine patients re-graded as D within 2.4 to 6.7 months (median, 4.2) (p = 0.006). Periablational hyperemia enhancements concealed all nine HCCs reevaluated as grade D. Conclusion: Side-by-side comparisons carry a risk of misleading diagnoses for LTP of HCC. Overlay fused imaging technology can be used to evaluate HCC ablative margin with high accuracy.

Introduction: Immune checkpoint inhibitors (ICIs) are promising agents for the treatment of hepatocellular carcinoma (HCC). However, the establishment of noninvasive measure that could predict the response to ICIs is challenging. This study aimed to evaluate tumor responses to ICIs using the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), which was shown to reflect Wnt/β-catenin activating mutation. Methods: A total of 68 intrahepatic HCC nodules from 18 patients with unresectable HCC and Child-Pugh class A liver function who received anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy were enrolled in this study. All patients had viable intrahepatic lesions evaluable using the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI within the 6 months prior to the treatment. The relative enhancement ratio was calculated, and the time to nodular progression (TTnP) defined as 20% or more increase in each nodule was compared between higher or hypo-enhancement HCC nodules. Then, the progression-free survival (PFS) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) were compared between patients with and without HCC nodules with higher enhancement on hepatobiliary phase images. Results: The median PFS was 2.7 (95% confidence interval [CI]: 1.4–4.0) months in patients with HCC nodules with higher enhancement (n = 8) and 5.8 (95% CI: 0.0–18.9) months in patients with hypointense HCC nodules (n = 10) (p = 0.007). The median TTnP of HCC nodules with higher enhancement (n = 23) was 1.97 (95% CI: 1.86–2.07) months and that of hypointense HCC nodules (n = 45) was not reached (p = 0.003). The ORR was 12.5% (1/8) versus 30.0% (3/10); the disease control rate was 37.5% (3/8) versus 70.0% (7/10), respectively, in patients with or without higher enhancement intrahepatic HCC nodules. Conclusion: The TTnP on HCC nodules with higher enhancement and the median PFS in patients who carried higher enhancement intrahepatic HCC nodules were significantly shorter than those in hypointense HCC nodules with anti-PD-1/PD-L1 monotherapy. The intensity of the nodule on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI is a promising imaging biomarker for predicting unfavorable response with anti-PD-1/PD-L1 monotherapy in patients with HCC.

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is typically associated with an extremely poor prognosis; however, small PDAC tumors show good prognosis. High-grade pancreatic intra-epithelial neoplasia (PanIN), which precedes invasive PDAC, is a primary target for improving the prognosis of PDAC. However, detection of high-grade PanIN without invasive carcinoma by existing imaging modalities is difficult because the lesions are only microscopically detectable. Recent studies have reported the characteristics of imaging findings associated with localized high-grade PanIN and the usefulness of serial pancreatic-juice aspiration cytologic examination as a method to confirm the pre-operative histopathology. In this review, we aimed to clarify recent clinical findings regarding detection of localized high-grade PanIN, which may contribute to improvement of the prognosis of patients with PDAC. Abstract Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions, such as pancreatic intra-epithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). The prognosis of high-grade precancerous lesions, including high-grade PanIN and high-grade IPMN, without invasive carcinoma is good, despite the overall poor prognosis of PDAC. High-grade PanIN, as a lesion preceding invasive PDAC, is therefore a primary target for intervention. However, detection of localized high-grade PanIN is difficult when using standard radiological approaches. Therefore, most studies of high-grade PanIN have been conducted using specimens that harbor invasive PDAC. Recently, imaging characteristics of high-grade PanIN have been revealed. Obstruction of the pancreatic duct due to high-grade PanIN may induce a loss of acinar cells replaced by fibrosis and lobular parenchymal atrophy. These changes and additional inflammation around the branch pancreatic ducts (BPDs) result in main pancreatic duct (MPD) stenosis, dilation, retention cysts (BPD dilation), focal pancreatic parenchymal atrophy, and/or hypoechoic changes around the MPD. These indirect imaging findings have become important clues for localized, high-grade PanIN detection. To obtain pre-operative histopathological confirmation of suspected cases, serial pancreatic-juice aspiration cytologic examination is effective. In this review, we outline current knowledge on imaging characteristics of high-grade PanIN.

Although programmed cell death protein 1 (PD&minus, 1)/PD-ligand 1 (PD-L1) blockade is effective in a subset of patients with hepatocellular carcinoma (HCC), its therapeutic response is still unsatisfactory. Alternatively, the potential impact of the lenvatinib in patients who showed tumor progression on PD&minus, 1/PD-L1 blockade is unknown. In this work, we evaluated the safety and efficacy of lenvatinib administration after PD-1/PD-L1 checkpoint blockade. The outcome and safety of lenvatinib administered after PD-1/PD-L1 blockade failure was analyzed retrospectively in 36 patients. Tumor growth was assessed every 4&ndash, 8 weeks using modified Response Evaluation Criteria in Solid Tumors. The mean relative dose intensity of lenvatinib was 87.6% and 77.8% in patients receiving a starting dose of 8 (interquartile range (IQR), 77.5&ndash, 100.0) mg and 12 (IQR, 64.4&ndash, 100.0) mg, respectively. Since lenvatinib therapy initiation, the median progression-free survival was 10 months (95% confidence interval (CI): 8.3&ndash, 11.8) and the median overall survival was 15.8 months (95% CI: 8.5&ndash, 23.2). The objective response rate was 55.6%, and the disease control rate was 86.1%. No particular safety concerns were observed. Lenvatinib demonstrated considerable antitumor effects with acceptable safety in patients with progressive and unresectable HCC when administered right after PD-1/PD-L1 blockade failure.

Purpose: To evaluate the efficacy and safety of transcatheter arterial embolization (TAE) for pseudoaneurysms occurring secondary to pancreatitis or because of leakage of pancreatic juice after pancreatectomy. Materials and Methods: This retrospective study included 42 consecutive patients (38 males and 4 females, mean age, 60 years, range, 33&ndash, 80 years) who underwent TAE for bleeding visceral artery pseudoaneurysms between March 2004 and December 2018. The technical and clinical success rates, incidence of recurrent bleeding, complications, including pancreatitis, and overall survival after TAE were evaluated. Results: Of the 42 enrolled patients, 23 had bleeding due to a complication of pancreatectomy and 19 had bleeding as a complication of pancreatitis. TAE with N-butyl cyanoacrylate (NBCA) or NBCA plus microcoils recurrent bleeding or inability to control bleeding was 15.8% (3 of 19) following TAE with NBCA and 17.4% (4 of 23) following TAE with coils. No clinically significant ischemic events of the pancreas or duodenum were observed in the embolized areas. Serum amylase did not increase compared with the initial levels after any of the procedures. At 30 days after TAE, 32 patients were alive. Conclusion: TAE has a high success rate for the management of hemorrhage, with few complications. The procedure appears to be safe and effective for pseudoaneurysms associated with either pancreatitis or pancreatectomy.

Background: This study aimed to evaluate and identify the specific CT findings by focusing on abnormalities in the main pancreatic duct (MPD) and pancreatic parenchyma in patients with small pancreatic cancer (PC) including carcinoma in situ (CIS). Methods: Nine CT findings indicating abnormalities of MPD and pancreatic parenchyma were selected as candidate findings for the presence of small PC ≤ 10 mm. The proportions of patients positive for each finding were compared between small PC and benign MPD stenosis groups. Interobserver agreement between two independent image reviewers was evaluated using kappa statistics. Results: The final analysis included 24 patients with small PC (including 11 CIS patients) and 28 patients with benign MPD stenosis. The proportion of patients exhibiting partial pancreatic parenchymal atrophy (PPA) corresponding to the distribution of MPD stenosis (45.8% vs. 7.1%, p < 0.01), upstream PPA arising from the site of MPD stenosis (33.3% vs. 3.6%, p = 0.01), and MPD abrupt stenosis (45.8% vs. 14.3%, p = 0.03) was significantly higher in the small PC group than in the benign MPD stenosis group. Conclusions: The presence of partial PPA, upstream PPA, and MPD abrupt stenosis on a CT image was highly suggestive of the presence of small PCs including CIS.

The aim of this study was to investigate the impact of radiologic experience on the diagnostic accuracy of computed tomography (CT) vs. magnetic resonance imaging (MRI) reporting on the liver metastases of pancreatic ductal adenocarcinoma (LM of PDAC). Intra-individual CT and MRI examinations of 112 patients with clinically proven LM of PDAC were included. Four radiologists with varying years of experience (A &gt, 20, B &gt, 5, C &gt, 1 and D &lt, 1) assessed liver segments affected by LM of PDAC, as well as associated metastases occurring in each patient. Their sensitivity and specificity in evaluating the segments were compared. Cohen's Kappa (&kappa, ) for diagnosed liver segments and Intra-class Correlation Coefficients (ICC) for the number of metastatic lesions in each patient were calculated. The radiologists&rsquo, sensitivity and specificity for the CT vs. MRI were, respectively: Reader A&mdash, 94.4%, 90.3% vs. 96.6%, 94.8%, B&mdash, 86.7%, 79.7% vs. 83.9%, 82.0%, C&mdash, 78.0%, 76.7% vs. 83.3%, 78.9% and D&mdash, 71.8%, 79.2% vs. 64.0%, 69.5%. Reviewers A and B achieved greater agreement in assessing results from the MRI (&kappa, = 0.72, p &lt, 0.001, ICC = 0.73, p &lt, 0.001) vs. the CT (&kappa, = 0.58, p &lt, ICC = 0.61, p &lt, 0.001), in contrast to readers C and D (MRI: &kappa, = 0.34, p &lt, ICC = 0.42, p &lt, 0.001, and CT: &kappa, = 0.48, p &lt, ICC = 0.59, p &lt, 0.001). Our results indicate that the accurate diagnosis of LM of PDAC depends more on radiologic experience in MRI over CT scans.

Tissue disaggregation and the cell sorting technique by surface markers has played an important role in isolating lymphatic endothelial cells (LECs) from lymphatic malformation (LM). However, this technique may have the drawback of impurities or result in isolation failure because it is dependent on surface marker expressions, the heterogeneity of which has been found in the lymphatic system. We developed a novel method for isolating LM-LECs without using whole tissue disaggregation. Seven LM surgical specimens were collected from seven patients with LMs. LM-LECs were detached from the LM cyst wall by “lumen digestion” and irrigating the cystic cavity with trypsin, and maintained in culture. The cells formed a monolayer with a cobblestone-like appearance. Immunohistochemistry and quantitative RT-PCR of these cells revealed high expression of lymphatic-specific genes, confirming their identity as LM-LECs. The whole-exome sequencing and PIK3CA sequencing of these cells revealed somatic mutations in PIK3CA in all cases. We established a novel technique for isolating LM-LECs from LM tissue by “lumen digestion” without whole-tissue disaggregation. The limited incorporation of non-LM LECs in the isolate in our method could make it an important tool for investigating the heterogeneity of gene expression as well as mutations in LM-LECs.

Objective COL4A1 variant causes severe central nervous system (CNS) anomalies, including hydranencephaly. However, the pathogenic mechanism underlying the COL4A1 phenotype remains unclear. Here, we report de novo COL4A1 variants in four Japanese patients with typical or rare CNS involvement and exhibiting diverse phenotypes. Methods We identified and enrolled four patients with white matter abnormalities and cerebral structural defects suggestive of cerebrovascular disease. Genetic analysis was performed using panel sequencing. Results All the patients were perinatally asymptomatic during the infantile period but exhibited developmental delay and growth retardation later. All the patients exhibited CNS symptoms, including psychomotor disability, spastic paralysis, and epilepsy. Brain magnetic resonance imaging revealed hydranencephaly (n = 1), ventriculomegaly (n = 4) associated with cerebral hemorrhage, and atretic encephalocele (n = 1). Three patients had developed congenital cataract, while two had hematuria. We identified two COL4A1 missense variants [exon32:c.2555G > A p.(Gly852Asp), exon40:c.3407G > A p.(Gly1136Asp)] and two in frame variants [exon32:c.2603_2609delinsATCCTGA p.(Ala868_Gly870delinsAspProGlu), exon36:c.3054delinsTGTAGAT p.(Leu1018delinsPheValAsp)]. The in frame variants were associated with severe CNS anomalies, hydranencephaly, and severe ventriculomegaly. Atretic encephalocele has never been reported in individuals with COL4A1 variants. Conclusions Our findings suggest that COL4A1 variants cause variable CNS symptoms. Association between clinical phenotypes and each COL4A1 variant would clarify their underlying etiologies.

AIM To investigate whether iodine density measurements from contrast-enhanced dual-energy computed tomography (CT) data can non-invasively stage liver fibrosis. METHODS This single-center, prospective study was approved by our IRB with written informed consent. Forty-seven consecutive patients (26 men and 21 women; mean age, 63.1 years) with chronic liver disease underwent contrast-enhanced dual-energy CT of the liver (non-contrast, arterial, portal venous, and equilibrium phase images), followed by liver biopsy. Iodine density of liver and aorta were obtained by two independent observers. Iodine uptake of the liver (Δ Liver), representing the difference in iodine density between equilibrium phase and non-contrast images, was calculated and normalized by aorta (Δ Liver/Aorta). We accounted for contrast agent distribution volume by using hematocrit level. Accuracy of iodine density measurements for staging liver fibrosis was assessed by using receiver operating characteristic (ROC) curves. Multivariate linear regression analysis was used to assess the impact of independent variables (liver fibrosis stage and patient-related confounders) on iodine uptake. RESULTS The Δ Liver/Aorta significantly increased and moderately correlated with METAVIR liver fibrosis stage (ρ = 0.645, P

Objective To elucidate the effect of prior use of ethinylestradiol on enzalutamide treatment for men with castration-resistant prostate cancer. Methods We retrospectively analyzed data from 99 consecutive patients (median age 72 years, range 50-88 years) treated with enzalutamide for castration-resistant prostate cancer between May 2014 and November 2015 after receiving several lines of hormonal therapy. Results A total of 45 patients were given ethinylestradiol before enzalutamide. The prostate-specific antigen response rate (decline in prostate-specific antigen >50% from baseline) of patients receiving ethinylestradiol and enzalutamide were 51.1% and 41.4%, respectively. Cross-resistance between ethinylestradiol and enzalutamide was clearly observed in the setting of pre-docetaxel. In multivariate analysis, the T stage and number of therapies before enzalutamide were the only significant predictors of prostate-specific antigen response to enzalutamide. However, in patients treated pre-docetaxel use, prior use of ethinylestradiol was a significant predictor of prostate-specific antigen response to enzalutamide, whereas ethinylestradiol did not affect the overall survival of these patients. Conclusions Cross-resistance between ethinylestradiol and enzalutamide in the setting of pre-docetaxel therapy seems to be evident. Therefore, ethinylestradiol should be used prudently before enzalutamide in this setting.

Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent.

To evaluate the diagnostic efficacy of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) vs. contrast-enhanced computed tomography (CE-CT) in the detection of liver metastasis in colorectal carcinoma patients.One-hundred fifty-eight consecutive patients with histopathologically confirmed colorectal carcinoma underwent EOB-MRI and CE-CT; 68 patients had 105 surgically confirmed liver metastases. Diagnostic analyses were performed according to sensitivity and positive predictive value (PPV) for liver metastasis detection in combined arterial- and hepatocyte-phase images vs. CE-CT by three readers blinded to clinical data. Diagnostic accuracy and sensitivity were evaluated using the alternative free-response receiver operating characteristic method.The overall sensitivity of EOB-MRI (91.4%) was significantly higher than that of CE-CT (80.9%, p 0.001); the higher sensitivity of EOB-MRI was observed especially in smaller-sized lesions (73.3 vs. 56.0% for lesions ≤1 cm; 91.9 vs. 80.8% for lesions1 cm and ≤2 cm; 99.2 vs. 95.7% for lesions2 cm). EOB-MRI showed a significantly greater area under the receiver operating characteristic curve (Az value = 0.970) compared with CE-CT (Az value = 0.899, p 0.01).EOB-MRI provided higher detectability for liver metastases, especially for smaller-sized lesions, than CE-CT in patients with colorectal carcinoma.

Silver nitrate instillation (SNI) is one form of treatment for chyluria. However, there is the opinion that a high volume of SNI (>10 mL) should be avoided because life-threatening complications have been reported. However, we have noticed that most severe complications occur in high-concentration treatments (≥1%), even with a small volume. In addition, a small volume (≤10 mL) of low-concentration (

Ellis-van Creveld syndrome (EvC MIM. #225500) is an autosomal recessive skeletal dysplasia characterised by thoracic hypoplasia, cardiac anomalies, acromesomelic limb shortening, and postaxial polydactyly. Affected individuals commonly manifest with cardiorespiratory failure as neonates but generally survive neonatal difficulties. We report here on affected Japanese sibs with a lethal phenotype of EvC caused by novel compound heterozygous mutations of EVC2, c.871-3 C > G and c.1991dupA.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.

A 56-year-old woman was diagnosed as having chronic obstructive pulmonary disease with heavy smoking. Mild pulmonary hypertension (mean pulmonary arterial pressure: 31 mmHg) was detected at the first visit. She was diagnosed with pulmonary hypertension due to pulmonary disease and medicated only with bronchodilators. Simultaneous, multiple freckling in the trunk of her body and café au lait macules in her back with some cutaneous neurofibromas were also detected. A plastic surgeon removed one of the neurofibromas and pathologically diagnosed it as neurofibromatosis type 1 (NF1). We finally rediagnosed her with pulmonary hypertension with unclear and/or multifactorial factors when she deteriorated 1 year after being treated only with bronchodilators. We then administrated upfront combination therapy with macitentan and tadalafil. Mean pulmonary arterial pressure rapidly improved. Learning Objective. Pulmonary arterial hypertension (PAH) in neurofibromatosis type 1 (NF1) can occur due to lung disease or due to certain involvement of pulmonary arteries, or a combination of both. Increased awareness of PAH in NF1 is very important for patients survival. The current therapeutic strategy is almost identical to that of idiopathic PAH; however, there is no clinical evidence. Insights gained from clinical experiences should help identify promising novel therapeutic approaches in NF1-PAH.

Nonalcoholic steatohepatitis (NASH) is a metabolic liver disease that progresses from simple steatosis to the disease state of inflammation and fibrosis. Previous studies suggest that apoptosis and necroptosis may contribute to the pathogenesis of NASH, based on several murine models. However, the mechanisms underlying the transition of simple steatosis to steatohepatitis remain unclear, because it is difficult to identify when and where such cell deaths begin to occur in the pathophysiological process of NASH. In the present study, our aim is to investigate which type of cell death plays a role as the trigger for initiating inflammation in fatty liver. By establishing a simple method of discriminating between apoptosis and necrosis in the liver, we found that necrosis occurred prior to apoptosis at the onset of steatohepatitis in the choline-deficient, ethionine-supplemented (CDE) diet model. To further investigate what type of necrosis is involved in the initial necrotic cell death, we examined the effect of necroptosis and ferroptosis inhibition by administering inhibitors to wild-type mice in the CDE diet model. In addition, necroptosis was evaluated using mixed lineage kinase domain-like protein (MLKL) knockout mice, which is lacking in a terminal executor of necroptosis. Consequently, necroptosis inhibition failed to block the onset of necrotic cell death, while ferroptosis inhibition protected hepatocytes from necrotic death almost completely, and suppressed the subsequent infiltration of immune cells and inflammatory reaction. Furthermore, the amount of oxidized phosphatidylethanolamine, which is involved in ferroptosis pathway, was increased in the liver sample of the CDE diet-fed mice. These findings suggest that hepatic ferroptosis plays an important role as the trigger for initiating inflammation in steatohepatitis and may be a therapeutic target for preventing the onset of steatohepatitis.

BACKGROUND Differentiation between inflammation and fibrosis is an important clinical distinction in patients with chronic liver disease, which has been difficult so far with MR elastography. PURPOSE To investigate whether dual-frequency MR elastography can estimate necroinflammation of the liver and improve diagnostic performance for the staging of liver fibrosis. STUDY TYPE Retrospective. SUBJECTS In all, 30 patients (14 males, 16 females) with chronic liver disease. FIELD STRENGTH/SEQUENCE 1.5T/dual-frequency MR elastography at 60-Hz and 80-Hz vibration frequencies. [Correction added on November 12, 2019, after first online publication: The field strength in the preceding sentence was corrected.] ASSESSMENT: Necroinflammation activity and fibrosis were assessed using the METAVIR scoring system. Stiffness values at 60-Hz (G60-Hz ) and 80-Hz (G80-Hz ) were obtained with an MR elastogram. The difference value between G80-Hz and G60-Hz (ΔG) was calculated. Four values (G60-Hz , G80-Hz , G60-Hz - ΔG, and G80-Hz + ΔG) were generated to estimate necroinflammation and fibrosis. STATISTICAL TESTS The ΔG were correlated with necroinflammation activity grade and fibrosis stage using Spearman's rank correlation. Diagnostic performance of the four values for necroinflammation activity grade and fibrous stage was assessed by using area under the receiver operating characteristic curve (AUC). RESULTS The mean value of G80-Hz (6.23 ± 3.67 kPa) was significantly higher than that of G60-Hz (5.27 ± 3.14 kPa) (P