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The aim of this study was to compare the incremental prognostic value of coronary computed tomography (CT) angiography (CCTA)-derived machine learning fractional flow reserve CT (ML-FFRct) versus that of ischemia detected on single-photon emission-computed tomography (SPECT) myocardial perfusion imaging (MPI) on incident cardiovascular outcomes.SPECT MPI and ML-FFRct are noninvasive tools that can assess the hemodynamic significance of coronary atherosclerotic disease.We studied a retrospective cohort of consecutive patients who underwent clinically indicated CCTA and SPECT MPI. ML-FFRct was computed using a ML prototype. The primary outcome was all-cause mortality and nonfatal myocardial infarction (D/MI), and the secondary outcome was D/MI and unplanned revascularization, percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) occurring more than 90 days postimaging. Multiple nested multivariate cox regression was used to model a scenario wherein an initial anatomical assessment was followed by a functional assessment.A total of 471 patients (mean age: 64 ± 13 year; 53% males) were included. Comorbidities were prevalent (78% hypertension, 66% diabetes, 81% dyslipidemia). ML-FFRct was 0.8 in at least 1 proximal/midsegment was present in 41.6% of patients, and ischemia on MPI was present in 13.8%. After a median follow-up of 18 months, 7% of patients (n = 33) experienced D/MI. On multivariate Cox proportional analysis, the presence of ischemia on MPI but not ML-FFRct significantly predicted D/MI (HR: 2.3; 95% CI: 1.0-5.0; P = 0.047; or HR: 0.7; 95% CI: 0.3-1.4; P = 0.306 respectively) when added to CCTA obstructive stenosis. Furthermore, the model with SPECT ischemia had higher global chi-square result and significantly improved reclassification. Results were similar using the secondary outcome and on several sensitivity analyses.In a high-risk patient cohort, SPECT MPI but not ML-FFRct adds independent and incremental prognostic information to CCTA-based anatomical assessment and clinical risk factors in predicting incident outcomes.

Background New data suggests long term outcomes of coronary revascularization based on instantaneous wave free ratio (iFR) are equivalent to invasive fractional flow reserve (FFR). We aimed to evaluate the correlation between non-invasive FFR derived from cardiac CT (FFR CT) and iFR. Methods Data from 21 patients with 26 vessels, who underwent both FFRCT computation and invasive iFR measurement, were analysed. We evaluated diagnostic performance of FFRCT according to two cut-off values of ≤0.80 and ≤0.70 with iFR ≤0.89 as the reference standard. Results In a per vessel analysis, the average diameter stenosis was 59%, mean FFRCT was 0.81 while mean iFR was 0.90. Using an FFRCT cut-off of 0.80, the sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy for FFRCT were 86%, 84%, 67%, 94%, and 85% respectively. When the cut-off was lowered to 0.70, the sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy for FFRCT were 57%, 100%, 100%, 86% and 88% respectively. Conclusion FFRCT correlates well with iFR in this small retrospective study. Larger studies are required to confirm this finding.

Colorectal cancer (CRC) has become the third most common cause of cancer-related deaths. CRC occurs because of abnormal growth of cells that can invade other tissues and cause distant metastases. Researchers have suggested that aberrant microRNA (miRNA) expression is involved in the initiation and progression of cancers. However, the key miRNAs that regulate the growth and metastasis of CRC remain unclear. The circulating miRNAs from BALB/c mice with CRC CT26 cell implantation were assayed by microarray. Then, Mus musculus (house mouse) mmu-miR-762 mimic and inhibitor were transfected to CT26 cells for analysis of cell viability, invasion, and epithelial-mesenchymal transition (EMT), cell cycle, and regulatory molecule expression. Human subjects were included for comparison the circulating Homo sapiens (human) has-miR-762 levels in CRC patients and control donors, as well as the patients with and without distant metastasis. The result for miRNA levels in mice with CRC cell implantation indicated that plasma mmu-miR-762 was upregulated. Transfection of mmu-miR-762 mimic to CT26 cells increased cell viability, invasion, and EMT, whereas transfection of mmu-miR-762 inhibitor decreased the above abilities. Cells treated with high-concentration mmu-miR-762 inhibitor induced cell cycle arrest at G0/G1 phase. However, mmu-miR-762 did not cause apoptosis of cells. Western blot analysis showed that mmu-miR-762 mimic transfection upregulated the expression of Wnt-1 and β-catenin, as well as increased the nuclear translocation of β-catenin. Further analysis was performed to demonstrate the correlation of miR-762 with CRC, and blood samples were collected from CRC patients and control donors. The results showed that serum has-miR-762 levels in CRC patients were higher than in control donors. Among the CRC patients (n= 20), six patients with distant metastasis showed higher serum has-miR-762 levels than patients without distant metastasis. Conclusions, the present study suggests that circulating miR-762 might be a potential biomarker for upregulation of CRC cell growth and invasion, and may be accompanied by the Wnt/β-catenin signaling.

Traumatic spinal cord injury (SCI) is a devastating condition marked by permanent motor, sensory, and autonomic dysfunction, in which the inflammatory response serves an important and preventable role. High mobility group box-1 (HMGB1) is a potent regulator of inflammation in numerous acute and chronic inflammatory conditions.; however, the role of HMGB1 in SCI remains unclear. The present study aimed to characterize the temporal dynamics of HMGB1 release after SCI, to investigate the role of spinal microglia activation in mediating the effects of HMGB1 on SCI, and to explore the therapeutic potential of intrathecal anti-HMGB1 polyclonal antibody on alleviating SCI. The present study demonstrated that HMGB1 expression was increased immediately after traumatic injury of a primary spinal neuron culture. It was found that neutralizing HMGB1 significantly ameliorated SCI pathogenesis and hind limb paralysis. Moreover, the levels of a number of pro-inflammatory cytokines in the SCI lesion were reduced when local HMGB1 was blocked by anti-HMGB1 antibody. In addition, the injured neuron-derived conditioned medium increased TNF-α secretion and the NF-κB pathway in the BV2 microglia cell line via HMGB1. Collectively, these results indicated that HMGB1 served an important role in SCI inflammation and suggested the therapeutic potential of an anti-HMGB1 antibody for SCI.

The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial showed no difference in outcomes between medical therapy vs coronary revascularization in the management of patients with stable coronary artery disease. We aimed to determine the percentage of patients with at least moderate ischemia that would have been eligible for enrollment and evaluate the outcomes of those who would not. Consecutive patients who underwent cardiac single-photon emission computed tomography (SPECT) between April 2016 and September 2019 were identified and all-cause mortality was determined. There were a total of 1508 patients (mean age 67 ± 11.6 years, 69.5% males) with any perfusion defect on SPECT. Patients had a high prevalence of cardiac risk factors (73.4% with hypertension and 54.4% with diabetes mellitus.) Nearly half (709, 47%) had moderate-to-severe ischemia but over two-thirds (479/709, 66.3%) had at least one ISCHEMIA trial exclusion criteria. Patients meeting ISCHEMIA enrollment criteria had a significantly lower all-cause mortality than those who would have been excluded (3.91% vs. 11.3%, respectively, P

Acute myocardial infarction (AMI) is a major cause of death worldwide. In the USA, there are approximately 0.8 million persons suffering from AMI annually with a death rate of 27%. The risk factors of AMI include hypertension, family history, smoking habits, diabetes, serenity, obesity, cholesterol, alcoholism, coronary artery disease, and so forth. In this study, data acquired from a subset of the National Health Insurance Research Database (NHIRD) of Taiwan were used to develop a clinical decision support system (CDSS) to predict AMI. The integrated genetic algorithm and support vector machine (IGS) and deep neural network (DNN) were both applied to design the predictive models. A balanced dataset (6087 AMI patients and 6087 non-AMI patients) and an imbalanced dataset (6,087 AMI patients and 12,174 non-AMI patients) with each patient record including 74 features were retrieved to design the predictive models. Tenfold cross-validation was used to obtain the optimal model with best prediction performance during training. The experimental results showed that the CDSSs reached a prediction performance with accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of 79.75–84.4%, 68.29–83.7%, 82.45–92.07%, and 0.8424–0.9089, respectively, for models designed based on the balanced dataset, as well as 81.86–86.27%, 52.65–81.22%, 84.29–96.47%, and 0.8503–0.9098, respectively, for models implemented based on the imbalanced dataset. The IGS and DNN algorithms and a combination of age, presence of related comorbidities, and other comorbidity-related features, including diagnosed age and annual physician visits of individual comorbidities, have been shown to be promising in designing strong predictive models in detecting patients who are more likely to develop AMI in the near future as well as for realizing mobile-health (m-Health) systems in managing their comorbidities to prevent occurrence of AMI events. Future work will focus on realizing an ensemble model by combining the model designed based on the long-term NHIRD dataset and the model based on the short-term EMR data and the real-time IoT sensor data, as well as implementing a transfer learning model by transferring the knowledge learned from the long-term model for training the short-term model, so that the predictive performance can be enhanced.

Background: Although ultrasound-guided needle decompression (US-GND) can treat calcific tendinitis of the shoulder effectively, repeat procedures might be required for unresolved symptoms. We evaluated the overall clinical outcomes of US-GND with subacromial steroid injection and the final results and factors predisposing toward repeat procedures.Methods: Ninety-eight patients who underwent US-GND for calcific tendinitis of the supraspinatus/infraspinatus were analyzed between March 2017 and December 2018. The clinical outcomes (pain visual analog scale, functional visual analog scale [FVAS], and American Shoulder and Elbow Surgeons [ASES] score) and final subjective satisfaction were compared between groups A (single US-GND) and B (repeat US-GND). The factors predisposing toward repeated US-GNDs were analyzed.Results: We found that 59.3% (58/98) of patient ASES scores were ≥80, and 73.5% of patients (72/98) were satisfied with the outcome. Group B (n=14) demonstrated a significantly higher rate of dominant-arm involvement compared to group A (78.6% vs. 48.8%, P=0.046). However, initial calcification size, shape, number, density, subscapularis involvement, lavage, and procedure time did not differ significantly between the groups. Group B showed poorer final FVAS (7 [interquartile range, 6–8] vs. 8 [interquartile range, 7–9], p=0.036) and subjective satisfaction compared to group A (satisfied: 5 [35.7%] vs. 67 [79.8%], p

BACKGROUND There is increasing interest in noncontrast-enhanced MRI due to safety concerns for gadolinium contrast agents. PURPOSE To investigate the clinical feasibility of MR-based conductivity imaging for breast cancer detection and lesion differentiation. STUDY TYPE Prospective. SUBJECTS One hundred and ten women, with 112 known cancers and 17 benign lesions (biopsy-proven), scheduled for preoperative MRI. FIELD STRENGTH/SEQUENCE Non-fat-suppressed T2-weighted turbo spin-echo sequence (T2WI), dynamic contrast-enhanced MRI and diffusion-weighted imaging (DWI) at 3T. ASSESSMENT Cancer detectability on each imaging modality was qualitatively evaluated on a per-breast basis: the conductivity maps derived from T2WI were independently reviewed by three radiologists (R1-R3). T2WI, DWI, and pre-operative digital mammography were independently reviewed by three other radiologists (R4-R6). Conductivity and apparent diffusion coefficient (ADC) measurements (mean, minimum, and maximum) were performed for 112 cancers and 17 benign lesions independently by two radiologists (R1 and R2). Tumor size was measured from surgical specimens. STATISTICAL TESTS Cancer detection rates were compared using generalized estimating equations. Multivariable logistic regression analysis was performed to identify factors associated with cancer detectability. Discriminating ability of conductivity and ADC was evaluated by using the areas under the receiver operating characteristic curve (AUC). RESULTS Conductivity imaging showed lower cancer detection rates (20%-32%) compared to T2WI (62%-71%), DWI (85%-90%), and mammography (79%-88%) (all P

Interstitial cystitis/bladder pain syndrome (IC/BPS) and irritable bowel syndrome (IBS) often occur concomitantly without an obvious reason. It is important to determine the relationship between these related diseases. We aimed to determine whether IBS increase the risk of IC/BPS. We identified newly diagnosed IBS patients between 2002 and 2013 from a nationwide database as the IBS cohort. Subjects diagnosed with IC/BPS before IBS were excluded. Cox’s regression analysis with a hazard ratio (HR) of IC/BPS between IBS and the non-IBS cohort was applied to unmatched and matched (16 confounders of propensity scores) models. The time from diagnosis of IBS to IC/BPS was also calculated. In the unmatched group, which included 100,124 IBS (55% female) and 874,048 non-IBS patients, the IC/BPS adjusted HR was 1.292 (95% confidence interval [CI], 1.131–1.476;p < 0.0001) in the IBS cohort compared with the non-IBS cohort. In the matched group, there were 85,359 patients in each cohort, and the IC/BPS HR was 1.599 (95% CI, 1.344–1.903; p < 0.0001). The average numbers of years until the development of IC/BPS in the IBS cohort and non-IBS cohort were 4.60 ± 2.58 (n = 253) and 5.99 ± 3.49 (n = 295) years, respectively. IBS was shown to increase the risk of IC/BPS in this 12-year cohort study. The time from the diagnosis of IBS to IC/BPS was 5.35 ± 3.18 years. A common pathophysiology of IBS and IC/BPS is possible. Clinicians should be mindful of the association and promote collaborative care of these two elusive diseases.

Background. To explore the role of natural killer (NK) cells in the process of hepatitis B virus (HBV) clearance and whether their phenotype is related to antiviral treatment outcome in chronic hepatitis B (CHB) patients. Method. We performed a single-center prospective cohort study to analyze changes of NK cells at weeks 12 and 24 from baseline in CHB patients who received PEGylated-interferon- (PEG-IFN-) α-2a versus entecavir. The frequencies of NK, CD56bright, CD56dim, IFNAR2+, NKp46+, NKp46bright, and NKp46dim NK cells and mean fluorescence intensity (MFI) of receptors NKp46 and IFNAR2 on the surface of NK cells were measured. Subgroup analyses were performed by comparing treatment responders versus nonresponders with aforementioned parameters in each group. Results. In PEG-IFN-α-treated patients, posttreatment CD56bright NK cell frequency increased, but CD56dim NK cell frequency decreased. Additionally, receptor NKp46 and IFNAR2 expression enhanced. In entecavir-treated patients, although NK cell frequency increased, CD56bright and CD56dim NK cell frequencies and IFNAR2 expression did not differ between baseline and posttreatment. In subgroup analyses, posttreatment CD56bright NK cell frequency and IFNAR2 expression significantly increased in PEG-IFN-α responders from baseline, while changes were absent in PEG-IFN-α nonresponders and entecavir treatment responders. Among patients with HBV viremia after entecavir therapy, NK cell frequency significantly increased, whereas NKp46bright and IFNAR2+ NK frequency and IFNAR2 MFI significantly decreased at 12 and 24 weeks from baseline. Conclusions. In CHB patients, PEG-IFN-α treatment significantly enhanced NK cell frequency and function when compared to entacavir. Positive treatment responses to either interferon or entecavir were associated with NK cell function improvement. This trial is registered with clinical trial registration no. NCT03208998.

To investigate clinical and imaging features associated with a high nodal burden (≥ 3 metastatic lymph nodes [LNs]) and compare diagnostic performance of US and MRI in patients with invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). Retrospective search revealed 239 patients with ILC and 999 with IDC who underwent preoperative US and MRI between January 2016 and June 2019. Patients with ILC were propensity-score-matched with patients with IDC. Univariate and multivariate logistic regression analyses were performed to determine factors associated with ≥ 3 metastatic LNs. 412 patients (206 ILC and 206 IDC) were evaluated. Of all patients with ILC, 27.2% (56/206) were node-positive and 7.8% (16/206) showed a high nodal burden. In multivariate analysis, the clinical N stage was the only independent factor associated with a high nodal burden in patients with IDC (odds ratio [OR] 6.24; 95% confidence interval [CI] 1.57–24.73; P = 0.009), but not in patients with ILC. Increased cortical thickness with loss of fatty hilum on US was associated with a high nodal burden in patients with ILC (OR 58.40; 95% CI 5.09–669.71; P = 0.001) and IDC (OR 24.14; 95% CI 3.52–165.37; P = 0.001), while suspicious LN findings at MRI were independently associated with a high nodal burden in ILC only (OR 13.94; 95% CI 2.61–74.39; P = 0.002). In patients with ILC, MRI findings of suspicious LNs were helpful to predict a high nodal disease burden.

Dictamnine is an active pharmaceutical ingredient in Dictamnus dasycarpus, a Chinese herbal medicine widely used for the treatment of skin inflammations such as atopic dermatitis (AD). Oxazolone has been demonstrated to induce significant skin inflammation and produce inflammatory cytokine expression identical to that of AD. An in vitro HaCaT inflammation model treated with dictamnine, which efficiently scavenged the reactive oxygen species (ROS) and mitochondrial ROS (mROS), and it reduced interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) expression, NLRP3 inflammasome activation, and NF-κB expression. To explore the anti-inflammatory mechanism of dictamnine and enhance sustained drug release and penetration into epidermal structures in a dermatitis mouse model, we prepared PLGA-nanocarrier-encapsulated dictamnine (Dic-PLGA-NC) in a specifically designed bioreactor, namely an ultrasound composite streams-impinging mixer (U-SiM). Mouse dermatitis model was treated with Dic-PLGA-NC medication, spleens were collected to evaluate body weight ratio, and skin was retrieved for histological examination and two-photon microscopy. The data demonstrate that Dic-PLGA-NC efficiently penetrated the dermal layer, making it superior to naked dictamnine; moreover, it ameliorated the dermatitis symptoms and inflammatory cytokine expression in vivo. Dic-PLGA-NC produced using the U-SiM bioreactor could be used in new manufacturing processes for drugs to treat AD.

Background/Purpose This study aimed to evaluate geographic variations and differences in the prevalence of hypertriglyceridemia and hypercholesterolemia between Taiwan's townships. Methods The prevalence of hypertriglyceridemia and hypercholesterolemia was evaluated according to the geographic characteristics of the people in the Adult Preventive Service Program from 2009 to 2010. The prevalence of hypertriglyceridemia and hypercholesterolemia in 2009 and 2010 was used and divided into three groups. Then, all townships were classed as having a significantly high prevalence, low prevalence, or an undetermined prevalence. Results The mean prevalence of hypertriglyceridemia and hypercholesterolemia was 29.26% and 43.96%, respectively. Geographic variations were observed: 125 townships had a high prevalence of hypertriglyceridemia, 122 townships had a low prevalence of hypertriglyceridemia, 142 townships had a high prevalence of hypercholesterolemia, and 159 townships had a low prevalence. A higher prevalence of hypertriglyceridemia was noted in the aboriginal areas. Conclusion Geographic variations exist in the prevalence of hypertriglyceridemia, and hypercholesterolemia. Our findings indicate that the prevention and treatment services in these high prevalence areas should be a priority.

Objective To compare the performance of simulated abbreviated breast MRI (AB-MRI) and full diagnostic (FD)-MRI in distinguishing between benign and malignant lesions detected by MRI and investigate the features of discrepant lesions of the two protocols. Materials and Methods An AB-MRI set with single first postcontrast images was retrospectively obtained from an FD-MRI cohort of 111 lesions (34 malignant, 77 benign) detected by contralateral breast MRI in 111 women (mean age, 49.8. ± 9.8; range, 28–75 years) with recently diagnosed breast cancer. Five blinded readers independently classified the likelihood of malignancy using Breast Imaging Reporting and Data System assessments. McNemar tests and area under the receiver operating characteristic curve (AUC) analyses were performed. The imaging and pathologic features of the discrepant lesions of the two protocols were analyzed. Results The sensitivity of AB-MRI for lesion characterization tended to be lower than that of FD-MRI for all readers (58.8–82.4% vs. 79.4–100%), although the findings of only two readers were significantly different (p < 0.05). The specificity of AB-MRI for lesion characterization was higher than that of FD-MRI for 80% of readers (39.0–74.0% vs. 19.5–45.5%, p ≤ 0.001). The AUC of AB-MRI was comparable to that of FD-MRI for all readers (p > 0.05). Fifteen percent (5/34) of the cancers were false-negatives on AB-MRI. More suspicious margins or internal enhancement on the delayed phase images were related to the discrepancies. Conclusion The overall performance of AB-MRI was similar to that of FD-MRI in distinguishing between benign and malignant lesions. AB-MRI showed lower sensitivity and higher specificity than FD-MRI, as 15% of the cancers were misclassified compared to FD-MRI.

Although new generations of EGFR-tyrosine kinase inhibitors (EGFR-TKI) have been developed for the treatment of patients with non–small cell lung cancer (NSCLC) with EGFR-mutant tumors, TKI resistance often returns as a result of additional EGFR mutations. In addition to seeking for next-generation EGFR-TKI, developing novel EGFR-targeting strategies may hold the key to overcome the vicious cycle of TKI resistance. Endocan is known as a receptor tyrosine kinase ligand enhancer in tumorigenesis, but the impact of endocan on EGFR-driven NSCLC progression remains unknown. In this study, higher endocan levels were found in lung tumors compared with cancer-free tissues and correlated with poor prognosis in patients with NSCLC harboring mutant EGFR; circulating endocan levels were also significantly higher in patients with mutant EGFR. Endocan facilitated EGFR signaling via direct binding and enhancing of the EGF–EGFR interaction and supported the growth of tumors driven by mutated EGFR. Activated EGFR in turn upregulated expression of endocan via JAK/STAT3 and ERK/ELK cascades, thus forming a positive regulatory loop of endocan-EGFR signaling. On the basis of the binding region between endocan and EGFR, we designed therapeutic peptides and demonstrated promising therapeutic effects in xenografts harboring EGFR mutations including TKI-resistant T790M. Together, our findings highlight the novel interaction between endocan and EGFR and new opportunities to effectively target endocan-EGFR regulatory axis in patients with TKI-resistant NSCLC. Significance: Endocan is a novel and critical regulator of EGF/EGFR signaling and serves as an alternative target of EGFR-TKI resistance in NSCLC.

Background Antiviral therapy is recommended for patients with immune-active chronic hepatitis B (CHB) to decrease the risk of liver-related complications. However, the outcomes of the pegylated IFN-α (PEG-IFN-α) therapy vary among CHB patients. We aimed to identify factors that can influence the outcomes in CHB patients who received antiviral PEG-IFN-α monotherapy. Methods Thirty-two CHB patients who received PEG-IFN-α monotherapy were enrolled in this study. All of the patients underwent two liver biopsies at baseline and 6 months after the initiation of the therapy. CD8+ T cells, CD4+ T cells, CD68+ mononuclear cells, and PD-1 levels in the 64 liver biopsy specimens were examined via immunofluorescence. Results The overall median frequency of CD8+ T cells in the liver tissues of 32 CHB patients significantly decreased at 6 months after the therapy initiation (p +PD-1+ T cells significantly decreased at 6 months (p +PD-1− T cells had no significant difference. On the contrary, in the FIENR (no fibrosis and inflammation response and HBeAg seroconversion) group, CD8+PD-1− T cells significantly decreased after 6 months of PEG-IFN-α treatment (p +PD-1+ T cells had no significant difference. In addition, the levels of CD68+ mononuclear cells in the FIER group showed an overall increasing trend after treatment (p Conclusions The changes in the levels of CD8+PD-1+ T cells and CD68+ mononuclear cells may be related to the response to PEG-IFN-α therapy.

OBJECTIVE To compare the utility and diagnostic performance of automated breast ultrasound system (ABUS) with that of hand-held ultrasound (HHUS) in evaluating pure non-mass enhancement (NME) lesions on breast magnetic resonance imaging (MRI). MATERIALS AND METHODS One hundred twenty-six consecutive MRI-visible pure NME lesions of 122 patients with breast cancer were assessed from April 2016 to March 2017. Two radiologists reviewed the preoperative breast MRI, ABUS, and HHUS images along with mammography (MG) findings. The NME correlation rate and diagnostic performance of ABUS were compared with that of HHUS, and the imaging features associated with ABUS visibility were analyzed. RESULTS Among 126 pure NME lesions, 100 (79.4%) were malignant and 26 (20.6%) were benign. The overall correlation rate was 87.3% (110/126) in ABUS and 92.9% (117/126) in HHUS. The sensitivity and specificity were 87% and 50% for ABUS and 92% and 42.3% for HHUS, respectively, with no significant differences (p = 0.180 and 0.727, respectively). Malignant NME was more frequently visualized than benign NME lesions on ABUS (93% vs. 65.4%, p = 0.001). Significant factors associated with the visibility of ABUS were the size of NME lesions on MRI (p < 0.001), their distribution pattern (p < 0.001), and microcalcifications on MG (p = 0.027). CONCLUSION ABUS evaluation of pure NME lesions on MRI in patients with breast cancer is a useful technique with high visibility, especially in malignant lesions. The diagnostic performance of ABUS was comparable with that of conventional HHUS in evaluating NME lesions.

Axillary lymph node (LN) metastasis is the most important predictor of overall recurrence and survival in patients with breast cancer, and accurate assessment of axillary LN involvement is an essential component in staging breast cancer. Axillary management in patients with breast cancer has become much less invasive and individualized with the introduction of sentinel LN biopsy (SLNB). Emerging evidence indicates that axillary LN dissection may be avoided in selected patients with node-positive as well as node-negative cancer. Thus, assessment of nodal disease burden to guide multidisciplinary treatment decision making is now considered to be a critical role of axillary imaging and can be achieved with axillary US, MRI, and US-guided biopsy. For the node-positive patients treated with neoadjuvant chemotherapy, restaging of the axilla with US and MRI and targeted axillary dissection in addition to SLNB is highly recommended to minimize the false-negative rate of SLNB. Efforts continue to develop prediction models that incorporate imaging features to predict nodal disease burden and to select proper candidates for SLNB. As methods of axillary nodal evaluation evolve, breast radiologists and surgeons must work closely to maximize the potential role of imaging and to provide the most optimized treatment for patients.

Accurate prediction of pathologic complete response (pCR) in breast cancer using magnetic resonance imaging (MRI) and ultrasound (US)-guided biopsy may aid in selecting patients who forego surgery for breast cancer. We evaluated the accuracy of US-guided biopsy aided by MRI in predicting pCR in the breast after neoadjuvant chemotherapy (NAC). After completion of NAC, 40 patients with near pCR (either tumor size ≤ 0.5 cm or lesion-to-background signal enhancement ratio (L-to-B SER) ≤ 1.6 on MRI) and no diffused residual microcalcifications were prospectively enrolled at a single institution. US-guided multiple core needle biopsy (CNB) or vacuum-assisted biopsy (VAB) of the tumor bed, followed by standard surgical excision, was performed. Matched biopsy and surgical specimens were compared to assess pCR. The negative predictive value (NPV), accuracy, and false-negative rate (FNR) were analyzed. pCR was confirmed in 27 (67.5%) surgical specimens. Preoperative biopsy had an NPV, accuracy, and FNR of 87.1%, 90.0%, and 30.8%, respectively. NPV for hormone receptor-negative and hormone receptor-positive tumors were 83.3% and 100%, respectively. Obtaining at least 5 biopsy cores based on tumor size ≤ 0.5 cm and an L-to-B SER of ≤ 1.6 on MRI (27 patients) resulted in 100% NPV and accuracy. No differences in accuracy were noted between CNB and VAB (90% vs. 90%). Investigation using stringent MRI criteria and ultrasound-guided biopsy could accurately predict patients with pCR after NAC. A larger prospective clinical trial evaluating the clinical safety of breast surgery omission after NAC in selected patients will be conducted based on these findings.

Backgrounds Distally based perforator propeller flap from the lower leg region is a versatile local reconstructive technique for the foot and ankle defects. However, flap venous congestion remains a tough nut to crack. We hypothesize that raising an adipofascial flap with turnover mode of transposition can improve venous drainage and enhance flap safety. Methods Based on the 2 rows of septocutaneous perforators in the posterior distal third of the lower leg, distally based adipofascial flap was raised from medial sural region nourished by 1 perforator bundle from the posterior tibial artery or from the lateral sural region from the peroneal artery. The superficial dissection was performed in subdermal plane and deep in to the subfascial space. The flap was nourished by perforator-plus-adipofascial pedicle and turned over 180 degrees upside down to reach the distal wounds. One week later, a split-skin graft was used to cover the exposed fascial flap. Postoperatively, flap survival, complications, and patient functional recovery were evaluated. Results Distally based sural turnover adipofascial flaps were used in 12 cases with complicated wounds of the distal third lower leg, foot, and ankle region. All wounds were caused by trauma and experienced fracture implants fixation and 5 with osteomyelitis. The comorbidities include diabetes in 9 cases and smoking in 7. There were 8 medial ural flaps and 4 lateral sural flaps. The adipofiscial flaps measured from 6.0 cm × 5.0 cm to 17.0 cm × 6.0 cm (mean, 61.3 cm). Postoperatively, all flaps survived uneventfully without any complication such as flap ischemia and/or necrosis. Two minor donor site complications were encountered, one was postoperative hematoma, and another was hyperproliferative scar. After a mean of 14.6 months of follow-up, the adipofascial flap plus skin graft showed a durable esthetic coverage, with normal shoe wearing and walking. Conclusions Distally based sural adipofascial turnover flap is a simple and reliable wound coverage technique. It avoids venous congestion as usually seen in distally based fasciocutaneous flaps.

Background/purpose: Few studies exist investigating the effectiveness of radioiodine (RAI) therapy for hyperthyroidism patients in Asia. We herein investigated the real-world efficacy of single-dose RAI therapy in Taiwanese patients with Graves’ disease (GD). Methods: This is a retrospective study of 243 patients with GD recorded between 1989 and 2016 in a tertiary referral hospital. Eu- or hypothyroid after RAI therapy were defined as the successful group. Kaplan–Meier curve and cox-regression model were used for analysis of prognostic factors. Results: Of the 243 patients, 187 were females, with mean age of 46.9 ± 13.6 years. Most patients (63.8%) did not choose RAI as the first-line therapy. The median dose was 7 mCi, with a mean follow-up period of 107.1 ± 82.8 months. The overall success rate was 70.9%. Univariate analysis revealed calculated- or fixed-dose (P = 0.015), goiter size (P

Hip fractures are of great interest worldwide as the geriatric population continues to increase rapidly. Currently, surgeons prefer to use cephalomedullary nail for internal fixation of pertrochanteric/intertrochanteric fractures. This article summarizes 10 concepts in hip fracture treatment over the past 20 years, including fracture line mapping, proximal lateral wall and anterior cortex, posteromedial lesser trochanter-calcar fragment, anteromedial cortex support reduction, changes of fracture reduction after sliding and secondary stability, nail entry point and wedge-open deformity, tip-apex distance and calcar-referenced tip-apex distance, femoral anterior bowing and nail modification, long nails for wide medullary canal and large posterior coronal fragment, and postoperative stability score.

A 54-year-old woman with a mechanical mitral valve replacement presented with recurrent admissions for pneumonia and pulmonary edema. Multimodality imaging revealed mobile masses on the prosthesis and discrepant point of care and inpatient international normalized ratio levels owing to antiphospholipid antibody cross-reactivity on the outpatient assay. The prosthetic valve thromboses resolved with therapeutic anticoagulation. (Level of Difficulty: Beginner.), Graphical abstract, A 54-year-old woman with a mechanical MVR presented with recurrent admissions for pneumonia and pulmonary edema. Multimodality imaging revealed…

OBJECTIVE To evaluate the clinical utility of ultrafast dynamic contrast-enhanced (DCE)-MRI compared to conventional DCE-MRI by studying lesion conspicuity and size according to the level of background parenchymal enhancement (BPE). MATERIALS AND METHODS This study included 360 women (median age, 54 years; range, 26-82 years) with 361 who had undergone breast MRI, including both ultrafast and conventional DCE-MRI before surgery, between January and December 2017. Conspicuity was evaluated using a five-point score. Size was measured as the single maximal diameter. The Wilcoxon signed-rank test was used to compare median conspicuity score. To identify factors associated with conspicuity, multivariable logistic regression was performed. Absolute agreement between size at MRI and histopathologic examination was assessed using the intraclass correlation coefficient (ICC). RESULTS The median conspicuity scores were 5 at both scans, but the interquartile ranges were significantly different (5-5 at ultrafast vs. 4-5 at conventional, p < 0.001). Premenopausal status (odds ratio [OR] = 2.2, p = 0.048), non-mass enhancement (OR = 4.1, p = 0.001), moderate to marked BPE (OR = 7.5, p < 0.001), and shorter time to enhancement (OR = 0.9, p = 0.043) were independently associated with better conspicuity at ultrafast scans. Tumor size agreement between MRI and histopathologic examination was similar for both scans (ICC = 0.66 for ultrafast vs. 0.63 for conventional). CONCLUSION Ultrafast DCE-MRI could improve lesion conspicuity compared to conventional DCE-MRI, especially in women with premenopausal status, non-mass enhancement, moderate to marked BPE or short time to enhancement.

Aims/Introduction Diabetic nephropathy (DN) is a complication of diabetes mellitus that is characterized by the gradual loss of kidney function, which results in increased levels of albumin in the urine. The Pro12Ala polymorphism in the peroxisome proliferator‐activated receptor‐γ2 gene has been confirmed to improve insulin sensitivity, but its association with susceptibility to DN in patients with type 2 diabetes remains inconclusive. Materials and Methods To examine whether the Pro12Ala polymorphism leads to the development of DN, a case‐control study was carried out in 554 patients with type 2 diabetes. The genotypes of Pro12Ala polymorphism of the peroxisome proliferator‐activated receptor gamma 2 gene were analyzed by real‐time polymerase chain reaction with TaqMan® probe genotyping assay in all patients. Results The mean age of the study population was 57.7 ± 8.8 years, with average diabetes duration of 12.8 ± 6.9 years. The prevalence of albuminuria was 43.5%. The frequency of genotype Pro12Pro, Pro12Ala and Ala12Ala genotype were 92.6%, 7.0%, 0.4% in our study population, and 90.4%, 8.9% and 0.7% in normal urinary albumin‐to‐creatinine ratio group, respectively. The Ala carriers (Pro12Ala + Ala12Ala) had significantly lower urinary albumin‐to‐creatinine ratio (15.0 vs 20.5 mg/g, P = 0.001) and better renal function (estimated glomerular filtration rate 81.8 [69.8–97.6] vs 78.7 mL/min/1.73 m2 [61.6–96.2]; P = 0.05) compared with those with the genotype Pro12Pro. After adjustment for age, sex and other confounders, the odds ratio of albuminuria for the Ala12 allele was 0.428 (95% confidence interval 0.195–0.940, P = 0.034]). Conclusions Our results suggest that the peroxisome proliferator‐activated receptor gamma 2 Ala12 variant has significant protective effects against albuminuria and DN., The peroxisome proliferator‐activated receptor‐γ2 Ala12 variant has significant protective effects against albuminuria and diabetic nephropathy. These findings suggest that genetic screening can help in the development of personalized therapies for diabetes.

Background In patients who are expected to achieve axillary pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC), omission of axillary lymph node (LN) dissection could prevent morbidity and complications. Purpose To develop a clinical model to predict residual axillary LN metastasis in patients with clinically node-positive breast cancer after NAC by using MRI and US. Materials and Methods In this retrospective study, women with clinically node-positive breast cancer who were treated with NAC following surgery between January 2015 and September 2017 were included. The patients were randomly assigned to a test and validation set (7:3 ratio). Univariable and multivariable logistic regression analyses were performed to evaluate the independent predictors of residual axillary LN metastasis in the test set. A prediction risk score was developed based on the odds ratios from the multivariable analysis and validated in both sets. Results A total of 408 women were included (mean age ± standard deviation, 47.9 years ± 9.6). The axillary pCR rate was 56.6% (231 of 408). Independent predictors of residual axillary LN metastasis were clinical stage N2 or N3, presence of axillary lymphadenopathy at US after NAC, tumor size reduction less than 50% at MRI, Ki-67 negativity, hormone receptor positivity, and human epidermal growth factor receptor 2 negativity (all, P < .05). In a model using these predictors, the area under the receiver operating characteristic curve in the test and validation sets was 0.84 (95% confidence interval: 0.79, 0.88) and 0.78 (95% confidence interval: 0.70, 0.87), respectively. When the patients had a simplified risk score of 1, the false-negative rates ranged between 5%-10%. Conclusion A prediction model incorporating nodal status stage, US finding, MRI response, and molecular receptor status shows good diagnostic performance for residual axillary lymph node metastasis after neoadjuvant chemotherapy in patients with clinically node-positive breast cancer. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Whitman in this issue.

Hepatitis B surface antigen (HBsAg) loss is considered a functional cure in chronic hepatitis B (CHB). However, the durability of HBsAg loss after stopping treatment remains unknown. This study aimed to assess the sustained functional cure achieved by interferon therapy in hepatitis B envelope antigen (HBeAg)-negative CHB patients. In this prospective study, 176 HBeAg-negative CHB patients with functional cure were enrolled for 12 weeks of cessation treatment, and treatment information and baseline data were collected. Hepatitis B virus (HBV) biomarkers and clinical biochemical indicators were evaluated every 3 months; liver imaging examinations were performed every 3-6 months during the 48-week follow-up. The sustained functional cure was evaluated. After the 48-week follow-up, the sustained functional cure rate was 86.63%. The cumulative rates of HBsAg reversion and HBV DNA reversion were 12.79% and 2.33%, respectively. Consolidation treatment ≥ 12 weeks after HBsAg loss achieved a significantly higher rate of sustained functional cure and significantly lower rate of HBsAg reversion than consolidation treatment < 12 weeks (76.19% vs 90.00%, P = 0.022 and 23.81% vs 9.23%, P = 0.014, respectively). Patients with hepatitis B surface antibody (HBsAb) had higher rate of sustained functional cure than patients achieving HBsAg loss but without HBsAb (89.86% vs 73.53%, P = 0.012). Consolidation treatment ≥ 12 weeks (odds ratio [OR] 16.478; 95% confidence interval [CI], 2.135-127.151; P = 0.007) and high HBsAb levels (OR 8.312; 95% CI, 1.824-37.881; P = 0.006) were independent predictors of sustained functional cure. Results suggested that 12 weeks of consolidation therapy after HBsAg clearance and elevated HBsAb levels help to improve functional cure.

Testicular cancer is the most commonly diagnosed cancer in men at 15‐44 years of age, and radical orchidectomy combined with chemotherapy is currently considered as the standard treatment. However, drugs resistance and side effects that impact the quality of life for patients with testicular cancer have not been markedly improved in recent decades. In this study, we characterized the pharmacological exacerbation of the unfolded protein response (UPR), which is an effective approach to kill testicular cancer cells, by carrying out a clustering analysis of mRNA expression profiles and the immunobloting examination of cordycepin‐treated MA‐10 cells. The UPR is executed in response to endoplasmic reticulum stress to complement by an apoptotic response if the defect cannot be resolved. Results showed that cordycepin significantly modulated FoxO/P15/P27, PERK‐eIF2α (apoptotic), and the IRE1‐XBP1 (adaptive) UPR pathways. Interestingly, a fraction of MA‐10 cells survived after cordycepin treatment, the AKT, LC3 I/II, and MAPK signaling pathways were highly induced in attached cells as compared to the suspended cells, illustrating the drug resistance to cordycepin via activating AKT and MAPK pathways in MA‐10 cells. In summary, PERK‐eIF2α signaling pathway is required for pro‐apoptotic UPR in MA‐10 cell death following cordycepin treatment, suggesting a potential therapeutic application in treating testicular cancer. However, activation of AKT and MAPK pathways could possibly result in drug resistance to cordycepin in MA‐10 cells.

Highlights • FGF9 induced cell proliferation, EMT, migration, and invasion of mouse Lewis lung cancer (LLC) cells, in vitro. • FGF9 interacted with FGFR1 and activated FAK, AKT, and ERK/MAPK signal pathways, induced the expression of EMT key proteins (N-cadherin, vimentin, snail, MMP2, MMP3 and MMP13) and reduced the expression of E-cadherin. • FGF9 promoted liver metastasis of subcutaneous inoculated LLC tumor with tumor growth, angiogenesis, EMT and M2-macrophage infiltration in the tumor microenvironment. • The FGF9/LLC syngeneic animal model provides a useful tool for the mechanism studies of liver metastasis which is the worst prognostic factor for lung cancer patients with distant organ metastasis., Fibroblast growth factors 9 (FGF9) modulates cell proliferation, differentiation and motility for development and repair in normal cells. Abnormal activation of FGF9 signaling is associated with tumor progression in many cancers. Also, FGF9 may be an unfavorable prognostic indicator for non-small cell lung cancer patients. However, the effects and mechanisms of FGF9 in lung cancer remain elusive. In this study, we investigated the FGF9-induced effects and signal activation profiles in mouse Lewis lung carcinoma (LLC) in vitro and in vivo. Our results demonstrated that FGF9 significantly induced cell proliferation and epithelial-to-mesenchymal transition (EMT) phenomena (migration and invasion) in LLC cells. Mechanism-wise, FGF9 interacted with FGFR1 and activated FAK, AKT, and ERK/MAPK signal pathways, induced the expression of EMT key proteins (N-cadherin, vimentin, snail, MMP2, MMP3 and MMP13), and reduced the expression of E-cadherin. Moreover, in the allograft mouse model, intratumor injection of FGF9 to LLC-tumor bearing C57BL/6 mice enhanced LLC tumor growth which were the results of increased Ki67 expression and decreased cleaved caspase-3 expression compared to control groups. Furthermore, we have a novel finding that FGF9 promoted liver metastasis of subcutaneous inoculated LLC tumor with angiogenesis, EMT and M2-macrophage infiltration in the tumor microenvironment. In conclusion, FGF9 activated FAK, AKT, and ERK signaling through FGFR1 with induction of EMT to stimulate LLC tumorigenesis and hepatic metastasis. This novel FGF9/LLC allograft animal model may therefore be useful to study the mechanism of liver metastasis which is the worst prognostic factor for lung cancer patients with distant organ metastasis.

Background Breast density at mammography is an established risk factor for breast cancer, but it cannot be used to distinguish between glandular and fibrous tissue. Purpose To evaluate the association between the glandular tissue component (GTC) at screening breast US and the risk of future breast cancer in women with dense breasts and the association between the GTC and lobular involution. Materials and Methods Screening breast US examinations performed in women with no prior history of breast cancer and with dense breasts with negative findings from mammography from January 2012 to December 2015 were retrospectively identified. The GTC was reported as being minimal, mild, moderate, or marked at the time of the US examination. In women who had benign breast biopsy results, the degree of lobular involution in normal background tissue was categorized as not present, mild, moderate, or complete. The GTC-related breast cancer risk in women with a cancer diagnosis or follow-up after 6 months was estimated by using Cox proportional hazards regression. Cumulative logistic regression was used to evaluate the association between the GTC and lobular involution. Results Among 8483 women (mean age, 49 years ± 8 [standard deviation]), 137 developed breast cancer over a median follow-up time of 5.3 years. Compared with a minimal or mild GTC, a moderate or marked GTC was associated with an increased cancer risk (hazard ratio, 1.5; 95% CI: 1.05, 2.1; P = .03) after adjusting for age and breast density. The GTC had an inverse association with lobular involution; women with no, mild, or moderate involution had greater odds (odds ratios of 4.9 [95% CI: 1.5, 16.6], 2.6 [95% CI: 0.95, 7.2], and 1.8 [95% CI: 0.7, 4.6], respectively) of a moderate or marked GTC than those with complete involution (P = .004). Conclusion The glandular tissue component was independently associated with the future breast cancer risk in women with dense breasts and reflects the lobular involution. It should be considered for risk stratification during screening breast US. © RSNA, 2021 Online supplemental material is available for this article.

Simple Summary The hypoxic inducible factor 1A (HIF1A) pathway has been known to play an important role in tumor progression in various cancers, including lower-grade (Grade II/III) gliomas (LGGs). An in silico analysis using 34 genes associated with the activity of the HIF1A pathway demonstrated that the BICD cargo adaptor 1 (BICD1) gene is a potential prognostic marker in LGGs. Moreover, BICD1 gene (BICD1) expression was positively correlated with CD274, GSK3B, HGF, and STAT3 expression in LGGs. Importantly, BICD1 downregulation was significantly associated with well-known favorable prognostic markers, such as a higher Karnofsky performance score (KPS), IDH1/TP53/ATRX mutations, wild-type EGFR and younger patient age, in LGGs. Therefore, our findings present BICD1 as a new prognostic biomarker to more precisely predict the clinical outcomes of LGG patients in coordination with those well-known biomarkers. Abstract Although several biomarkers have been identified to predict the prognosis of lower-grade (Grade II/III) gliomas (LGGs), we still need to identify new markers to facilitate those well-known markers to obtain more accurate prognosis prediction in LGGs. Bioinformatics data from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and the Cancer Cell Line Encyclopedia (CCLE) datasets were used as the research materials. In total, 34 genes associated with the HIF1A pathway were analyzed using the hierarchical method to search for the most compatible gene. The BICD cargo adaptor 1 (BICD1) gene (BICD1) was shown to be significantly correlated with The hypoxic inducible factor 1A (HIF1A) expression, the World Health Organization (WHO) grade, and IDH1 mutation status. In addition, BICD1 downregulation was significantly correlated with a higher Karnofsky performance score (KPS), IDH1/TP53/ATRX mutations, wild-type EGFR, and younger patient age in the enrolled LGG cohort. Moreover, BICD1 expression was significantly upregulated in wild-type IDH1 LGGs with EGFR mutations. Kaplan–Meier survival analysis revealed that BICD1 downregulation predicts a favorable overall survival (OS) in LGG patients, especially in those with IDH1 mutations. Intriguingly, we found a significant correlation between BICD1 downregulation and a decreased level of CD274, GSK3B, HGF, or STAT3 in LGGs. Our findings suggest that BICD1 downregulation could be a potential biomarker for a favorable prognosis of LGGs.

Background: People with dementia are a high-risk group for hip fractures. Although the increased risk of hip fractures associated with antipsychotic drugs (APD) is found in older populations, little is known about the risk for people with dementia living in Asia. We aimed to investigate the association between hip fractures and the characteristics of APD use in patients with dementia. Methods: A nested case-control analysis was conducted on a nationwide cohort in Taiwan. People with diagnoses of dementia during 2003–2012 were identified. Conditional logistic regression analysis was performed, and adjusted odds ratios (aORs) were calculated with a 95% confidence interval (CI) to estimate the risk of hip fractures. Results: APD use was associated with an increased risk of hip fractures in patients with dementia, current use or combined use of first and second generations of APDs had even higher risks. Regarding the duration of APD use, a U-shape curve of hip fracture risk was noted, and the risk peaked during 0–15 days and &gt, 215 days of exposure (aOR = 1.46, 95% CI 1.37–1.57, aOR = 1.47, 95% CI 1.37–1.58, respectively). Considering the doses of APDs, the hip fracture risk was significantly increased with all four levels of the cumulative doses and average daily doses and peaked in the group with the highest average daily dose. Conclusions: The findings suggest that caution must be taken when initiating APD use in patients with dementia, even in a small dose, and mixed types of APD prescriptions should be administered with care. Furthermore, frequent evaluation of the possibility of tapering or withdrawal of the medication is necessary, as the risk does not attenuate after long-term use.

Background There is an increasing need to develop a more accurate prediction model for pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer. Purpose To develop a nomogram based on MRI and clinical-pathologic variables to predict pCR. Materials and Methods In this single-center retrospective study, consecutive women with stage II-III breast cancer who underwent NAC followed by surgery between January 2011 and December 2017 were considered for inclusion. The women were divided into a development cohort between January 2011 and September 2015 and a validation cohort between October 2015 and December 2017. Clinical-pathologic data were collected, and mammograms and MRI scans obtained before and after NAC were analyzed. Logistic regression analyses were performed to identify independent variables associated with pCR in the development cohort from which the nomogram was created. Nomogram performance was assessed with the area under the receiver operating characteristic curve (AUC) and calibration slope. Results A total of 359 women (mean age, 49 years ± 10 [standard deviation]) were in the development cohort and 351 (49 years ± 10) in the validation cohort. Hormone receptor negativity (odds ratio [OR], 3.1; 95% CI: 1.4, 7.1

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the oral cavity, and long non-coding (lnc)RNA of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was recently reported to play a crucial role in OSCC development and progression. However, potential effects of genetic variants of MALAT1 on the development of OSCC are still unclear. Herein, we performed a case-control study in 1350 patients with OSCC and 1199 healthy controls to evaluate the association between functional single-nucleotide polymorphisms (SNPs) of MALAT1 and OSCC susceptibility, as well as its clinicopathologic characteristics. A TaqMan allelic discrimination assay was used to genotype four tagging SNPs, viz., rs3200401 C>T, rs619586 A>G, rs1194338 C>A, and rs7927113 G>A, and results showed that the MALAT1 rs3200401 T allele had a lower risk of OSCC (adjusted odds ratio (AOR): 0.779, 95% confidence interval (CI): 0.632~0.960, p=0.019) and a higher risk of developing moderately (grade II)/poorly (grade III) differentiated OSCC (AOR: 1.508-fold, 95% CI: 1.049~2.169, p=0.027) under a dominant model. According to environmental carcinogen exposure, patients with a betel quid-chewing habit who carried the T allele of rs3200401 more easily developed high-grade (II/III) OSCC (AOR: 1.588, 95% CI: 1.055~2.390, p=0.027), and patients with the same genotype but who did not chew betel quid had a lower risk of developing lymph node metastasis (AOR: 0.437, 95% CI: 0.255~0.749, p=0.003). In addition to rs3200401, the rs619586 AG/GG genotype was associated with increased risks of developing advanced stages (III+IV) and larger tumor sizes (>T2) compared to the AA genotype, especially in the subgroup of betel quid chewers. Furthermore, analyses of clinical datasets revealed that the MALAT1 expression level was upregulated in OSCC compared to normal tissues, especially in the betel quid-chewing population. These results indicated involvement of MALAT1 SNPs rs3200401 and rs619586 in the development of OSCC and support the interaction between MALAT1 gene polymorphisms and the environmental carcinogen as a predisposing factor for OSCC progression.

MicroRNAs are small non-coding RNAs known to negative regulate endogenous genes. Some microRNAs have high sequence conservation and localize as clusters in the genome. Their coordination is regulated by simple genetic and epigenetic events mechanism. In cells, single microRNAs can regulate multiple genes and microRNA clusters contain multiple microRNAs. MicroRNAs can be differentially expressed and act as oncogenic or tumor suppressor microRNAs, which are based on the roles of microRNA-regulated genes. It is vital to understand their effects, regulation, and various biological functions under both normal and disease conditions. Head and neck squamous cell carcinomas are some of the leading causes of cancer-related deaths worldwide and are regulated by many factors, including the dysregulation of microRNAs and their clusters. In disease stages, microRNA clusters can potentially control every field of oncogenic function, including growth, proliferation, apoptosis, migration, and intercellular commutation. Furthermore, microRNA clusters are regulated by genetic mutations or translocations, transcription factors, and epigenetic modifications. Additionally, microRNA clusters harbor the potential to act therapeutically against cancer in the future. Here, we review recent advances in microRNA cluster research, especially relative to head and neck cancers, and discuss their regulation and biological functions under pathological conditions as well as translational applications.

Objective The aim of this study was to investigate the usefulness of staging chest-CT in terms of diagnostic yield and false-referral rate in patients with operable breast cancer. Materials and methods This study was approved by the institutional review border. In this retrospective study, we reviewed patients who underwent staging chest-CT between January 2014 and June 2016. Reference standard was defined as a combination of pathology and radiologic tumor changes in accordance with primary tumor or metastatic lesions and stability during the 12-month follow-up period. We calculated diagnostic yield and false-referral rates stratified by pathologic stage. The important ancillary findings of staging chest-CT were also recorded. Results A total of 1,342 patients were included in this study. Of these, four patients (0.3%; 4/1342) had true pulmonary metastasis. Diagnostic yields of stage I, II, III disease were 0.0% (0/521), 0.3% (2/693), and 1.6% (2/128), respectively. The overall false-referral rate was 4.6% (62/1342); false-referral rates of stage I, II, and III disease were 5.0% (26/521), 3.8% (26/693), and 7.8% (10/128), respectively. No occult thoracic metastasis occurred within 12 months of staging chest-CT. Nineteen patients showed significant ancillary findings besides lung metastasis, including primary lung cancer (n = 9). The overall diagnostic yield of ancillary findings was 1.7% (23 of 1342). Conclusions The incidence of pulmonary metastasis was near zero for pathologic stages I/II and slightly higher (although still low; 1.6%). for stage III. Considering its low diagnostic yield and substantial false-referral rates, staging chest-CT might not be useful in patients with operable breast cancer.

Background: The fasting blood glucose (FBG) values extracted from electronic medical records (EMR) are typically assumed to be valid in existing research, which may cause diagnostic bias. We proposed a machine learning (ML) algorithm to predict the fasting status of blood samples. Methods: We evaluated the distribution of BG values in the China Medical University Hospital Clinical Research Data Repository and established the theoretical fasting status when the ontologically labeled FBG was lower than the estimated average glucose calculated from HbA1c. In addition to logistic regression, we extracted 67 features to predict the fasting status by eXtreme Gradient Boosting (XGBoost). The discrimination and calibration of the prediction models were also assessed. Findings: Of the 784340 ontologically labeled fasting samples, 77·1% were considered theoretical FBGs. The median (IQR) glucose and HbA1c level of ontological and theoretical fasting samples in patients without diabetes mellitus (DM) were 110 mg/dL and 5·6%, and 92 mg/dL and 5·6%, respectively. In multiple logistic regression, 14 selected variables were significantly associated with the fasting status, but the area under the receiver operating characteristic curve (AUROC) was only 0·868. XGBoost showed better calibration and achieved an AUROC of 0·892 with the top five contributing predictors of glucose level, distance from home to hospital, age, height, and concomitantly prescribed serum creatinine. Interpretation: Our results demonstrated an innovative approach to clean EMR data and detect true FBG, which could aid more accurate estimation of the global and local epidemiology of DM. Funding: This study was supported by the Ministry of Science and Technology of Taiwan (grant number: 108-2314-B-039-038-MY3 and 109-2321-B-468-001) Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Research Ethical Committee/Institutional Review Board of China Medical University Hospital (CMUH105-REC3-068).

Summary Background Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide–dexamethasone and carfilzomib–dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib–dexamethasone versus carfilzomib–dexamethasone in patients with relapsed multiple myeloma. Methods This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib–dexamethasone (isatuximab group) or carfilzomib–dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285. Findings Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77–not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32–0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients. Interpretation The addition of isatuximab to carfilzomib–dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population. Funding Sanofi. Video Abstract Video abstractYouTube link: https://youtu.be/5kXtQQlzRh4

To prospectively evaluate the diagnostic performance of screening ABUS as the primary screening test for breast cancer among Korean women aged 40–49 years. This prospective, multicenter study included asymptomatic Korean women aged 40–49 years from three academic centers between February 2017 and October 2019. Each participant underwent ABUS without mammography, and the ABUS images were interpreted at each hospital with double-reading by two breast radiologists. Biopsy and at least 1 year of follow-up was considered the reference standard. Diagnostic performance of ABUS screening and subgroup analyses according to patient and tumor characteristics were evaluated. Reference standard data were available for 959 women. The recall rate was 9.8% (95% confidence interval [CI]: 7.9%, 11.7%; 94 of 959 women) and the cancer detection yield was 5.2 per 1000 women (95% CI: −0.6, 11.1; 5 of 959 women). There was only one interval cancer. The sensitivity was 83.3% (95% CI: 53.5%, 100%; 5 of 6 cancers) and the specificity was 90.7% (95% CI: 88.8%, 92.5%; 864 of 95. women). The positive predictive values of biopsies performed (PPV3) was 20.0% (95% CI: 4.3%, 35.7%; 5 of 25 women). Women with heterogeneous background echotexture had a higher recall rate (p = .009) and lower specificity (p = .036). Women with body mass index values < 25 kg/m2 had a higher mean recall rate (p = .046). In East Asia, screening automated breast US may be an alternative to screening mammography for detecting breast cancers in women aged 40–49 years. • Automated breast US screening for breast cancer in asymptomatic women aged 40–49 is effective with 5.2 per 1000 cancer detection yield. • Women with heterogeneous background echotexture had a higher recall rate and lower specificity. • Women with body mass index < 25 kg/m 2 had a higher recall rate.

Cancer metastasis is a central oncology concern that worsens patient conditions and increases mortality in a short period of time. During metastatic events, mitochondria undergo specific physiological alterations that have emerged as notable therapeutic targets to counter cancer progression. In this study, we use drug-free, cationic peptide fibrillar assemblies (PFAs) formed by poly(L-Lysine)-block-poly(L-Threonine) (Lys-b-Thr) to target mitochondria. These PFAs interact with cellular and mitochondrial membranes via electrostatic interactions, resulting in membranolysis. Charge repulsion and hydrogen-bonding interactions exerted by Lys and Thr segments dictate the packing of the peptides and enable the PFAs to display enhanced membranolytic activity toward cancer cells. Cytochrome c (cyt c), endonuclease G, and apoptosis-inducing factor were released from mitochondria after treatment of lung cancer cells, subsequently inducing caspase-dependent and caspase-independent apoptotic pathways. A metastatic xenograft mouse model was used to show how the PFAs significantly suppressed lung metastasis and inhibited tumor growth, while avoiding significant body weight loss and mortality. Antimetastatic activities of PFAs are also demonstrated by in vitro inhibition of lung cancer cell migration and clonogenesis. Our results imply that the cationic PFAs achieved the intended and targeted mitochondrial damage, providing an efficient antimetastatic therapy.

Nucleotides with add-on interferon treatment (NUC-IFN) provide significantly higher rates of hepatitis B surface antigen (HBsAg) loss in patients with chronic hepatitis B (CHB). This study aimed to investigate the sustainability of HBsAg loss and the prevention of clinical relapse.Patients with CHB who achieved HBsAg loss and HBV DNA levels20 IU/ml after IFN or NUC-IFN therapy were enrolled and followed up for 96 weeks. The primary outcome was HBsAg negativity without viremia at week 96. Secondary outcomes included virological or clinical relapse and predictors of relapse.420 patients were included in intention-to-treat analysis with 290 and 130 in the IFN and NUC-IFN groups respectively. At week 96, the intention-to-treat analysis revealed similar outcomes between groups, including HBsAg seroreversion (24.83% vs. 23.08%, P = .70), viremia (16.90% vs 13.08%, P = .32) and clinical relapse (11.38% vs 10.00%, P = .68); the per-protocol analyses also showed HBsAg seroreversion, viremia and clinical relapse in IFN group (15.50%, 6.59% and 0.39%) did not differ from those in NUC-IFN group (15.25%, 4.24% and 0.85%, P .05). These outcomes were similar between patients who received entecavir and those who received telbivudine/lamivudine/adefovir before the combination therapy. In NUC-IFN-treated patients, fibrosis regression was observed at week 96. Baseline HBsAb negativity was independent predictors of HBsAg sero-reversion and recurrence of viremia in IFN treated group.NUC-IFN and IFN therapies are equally effective in achieving sustained functional cure and fibrosis regression. (ClinicalTrials.gov, Number NCT02336399).

Highlights • There are protean manifestations of cardiac involvement with COVID 19 • Hemorrhagic pericardial effusion may be the sole cardiac manifestation of COVID 19

Recent studies on chronic viral infections have defined a novel programmed cell death 1-positive (PD-1(+)) T cell factor 1-positive (TCF1(+)) stem-like CD8 T cell subset that gives rise to the terminally differentiated exhausted CD8 T cells. In this study, we performed T cell receptor beta (TCRβ) sequencing of virus-specific CD8 T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection to examine the TCR diversity and lineage relationship of these two functionally distinct subsets. We found that >95% of the TCR repertoire of the exhausted CD8 T cell subset was shared with the stem-like CD8 T cells. The TCR repertoires of both CD8 T cell subsets were composed mostly of a few dominant clonotypes, but there was slightly more breadth and diversity in the stem-like CD8 T cells than their exhausted counterpart (∼40 versus ∼15 GP33(+) clonotypes; ∼20 versus ∼7 GP276(+) clonotypes). Interestingly, the breadth of the TCR repertoire was broader during the early stages (day 8) of the chronic infection than the later stages (days 45 to 60), showing that there was a narrowing of the TCR repertoire during chronic infection (∼2-fold GP33(+) and GP276(+) stem-like subset; ∼10-fold GP33(+) and ∼5-fold GP276(+) exhausted subset). In contrast, during acute LCMV infection, the TCR repertoire was much broader in both GP33-specific effector (∼160 clonotypes) and memory CD8 T cells (∼160 clonotypes). Overall, our data demonstrate that the virus-specific CD8 T cell TCR repertoire is broad and remains stable after acute LCMV infection, but it contracts and is narrower during chronic infection. Our study also shows that the repertoire of the exhausted CD8 T cell subset is almost completely derived from the stem-like CD8 T cell subset during established chronic LCMV infection. IMPORTANCE CD8 TCR repertoires responding to chronic viral infections (HIV, hepatitis C virus [HCV], Epstein-Barr virus [EBV], and cytomegalovirus [CMV]) have limited breadth and diversity. How these repertoires change and are maintained throughout the chronic infection are unknown. We thus characterized the LCMV-specific CD8 TCR repertoires of stem-like and terminally exhausted subsets generated during chronic LCMV infections. During chronic LCMV infections, the repertoires started as diverse but became more clonal at the late time point. Further, the exhausted subset was composed of dominant clonotypes that were shared with the stem-like subset. Together, we demonstrate that the TCR repertoire contracts over time and is almost exclusively derived from the stem-like subset late during the persistent viral infection. Our data suggest that dominant clonotypes in the exhausted subset are derived from a diverse pool of stem-like clonotypes, which may be contributing to the clonality observed during chronic viral infections.

Background: Increasing evidence suggests a link between the gut microbiome and various diseases including hypertension and chronic kidney disease (CKD). However, studies examining the efficacy of controlling blood pressure and inhibiting the renin–angiotensin system (RAS) in preventing CKD progression are limited. Methods: In the present study, we used 5/6 nephrectomised (NX) and unilateral ureteral obstructed (UUO) rat models and cultured renal tubular epithelial cells and fibroblasts to test whether alisol B 23-acetate (ABA) can attenuate renal fibrogenesis by regulating blood pressure and inhibiting RAS. Results: ABA treatment re-established dysbiosis of the gut microbiome, lowered blood pressure, reduced serum creatinine and proteinuria, suppressed expression of RAS constituents and inhibited the epithelial-to-mesenchymal transition in NX rats. Similarly, ABA treatment inhibited expression of collagen I, fibronectin, vimentin, α-smooth muscle actin and fibroblast-specific protein 1 at both mRNA and protein levels in UUO rats. ABA was also effective in suppressing activation of the transforming growth factor-β (TGF-β)/Smad3 and preserving Smad7 expression in both NX and UUO rats. In vitro experiments demonstrated that ABA treatment inhibited the Wnt/β-catenin and mitochondrial-associated caspase pathways. Conclusion: These data suggest that ABA attenuated renal fibrosis through a mechanism associated with re-establishing dysbiosis of the gut microbiome and regulating blood pressure, and Smad7-mediated inhibition of Smad3 phosphorylation. Thus, we demonstrate ABA as a promising candidate for treatment of CKD by improving the gut microbiome and regulating blood pressure.