The active form of vitamin D (calcitriol) promotes CXCR5 expression during follicular helper T cell differentiation.

Follicular helper T (Tfh) cells promote B cell differentiation and antibody production in the B cell follicles of secondary lymphoid organs. Tfh cells express their signature transcription factor BCL6, interleukin (IL)-21, and surface molecules including inducible T cell costimulator, programmed cell death-1 (PD-1), and the chemokine receptor CXCR5. Migration of Tfh cells to B cell follicles largely depends on the CXCR5 expression induced by interactions with antigen-presenting dendritic cells in the T cell area. How Tfh cells acquire sufficient levels of CXCR5 expression, however, has remained unclear. Using our in vitro culture system to generate CXCR5low Tfh-like cells from naïve CD4+ T cells with IL-6 in the absence of other cell types, we found that the active form of vitamin D, calcitriol, markedly enhanced CXCR5 expression after the release from persistent T cell receptor (TCR) stimulation. CH-223191, an aryl hydrocarbon receptor antagonist, further enhanced CXCR5 expression. IL-12 but not IL-4, in place of IL-6, also supported calcitriol to enhance CXCR5 expression even before the release from TCR stimulation, whereas the cell viability sharply decreased after the release. The Tfh-like cells generated with IL-6 and calcitriol exhibited chemotaxis towards CXCL13, expressed IL-21, and helped B cells to produce IgG antibodies in vitro more efficiently than Tfh-like cells generated without added calcitriol. Calcitriol injections into antigen-primed mice increased the proportion of CXCR5+PD-1+CD4+ cells in their lymphoid organs, and enhanced T cell entry into B-cell follicles. These results suggest that calcitriol promotes CXCR5 expression in developing Tfh cells and regulates their functional differentiation.

Efficacy of GV1001 with gemcitabine/capecitabine in previously untreated patients with advanced pancreatic ductal adenocarcinoma having high serum eotaxin levels (KG4/2015): an open-label, randomised, Phase 3 trial.

BACKGROUND: The TeloVac study indicated GV1001 did not improve the survival of advanced pancreatic ductal adenocarcinoma (PDAC). However, the cytokine examinations suggested that high serum eotaxin levels may predict responses to GV1001. This Phase III trial assessed the efficacy of GV1001 with gemcitabine/capecitabine for eotaxin-high patients with untreated advanced PDAC. METHODS: Patients recruited from 16 hospitals received gemcitabine (1000 mg/m2, D 1, 8, and 15)/capecitabine (830 mg/m2 BID for 21 days) per month either with (GV1001 group) or without (control group) GV1001 (0.56 mg; D 1, 3, and 5, once on week 2-4, 6, then monthly thereafter) at random in a 1:1 ratio. The primary endpoint was overall survival (OS) and secondary end points included time to progression (TTP), objective response rate, and safety. RESULTS: Total 148 patients were randomly assigned to the GV1001 (n = 75) and control groups (n = 73). The GV1001 group showed improved median OS (11.3 vs. 7.5 months, P = 0.021) and TTP (7.3 vs. 4.5 months, P = 0.021) compared to the control group. Grade >3 adverse events were reported in 77.3% and 73.1% in the GV1001 and control groups (P = 0.562), respectively. CONCLUSIONS: GV1001 plus gemcitabine/capecitabine improved OS and TTP compared to gemcitabine/capecitabine alone in eotaxin-high patients with advanced PDAC. CLINICAL TRIAL REGISTRATION: NCT02854072.

Randomized Trial of Prophylactic Antibiotics for Endoscopic Retrograde Cholangiopancreatography in Patients With Biliary Obstruction.

INTRODUCTION: The incidence of postendoscopic retrograde cholangiopancreatography (ERCP) infections is reported to be up to 18% in patients with biliary obstruction. Antibiotic prophylaxis may reduce the risk of infectious complications after ERCP; however, the clinical value of prophylactic antibiotics in ERCP remains controversial. METHODS: We conducted a double-blind, placebo-controlled, randomized trial to investigate whether the use of prophylactic antibiotics would reduce infectious complications after ERCP in patients with biliary obstruction. We randomly assigned patients in a 1:1 ratio to receive either a single dose of 1 g intravenous cefoxitin or normal saline as a placebo 30 minutes before undergoing ERCP. The primary outcome was the incidence of infectious complications after ERCP. RESULTS: We enrolled 378 patients, and 189 patients were assigned to each group. The risk of infectious complications after ERCP was 2.8% (5 of 176 patients) in the antibiotic prophylaxis group and 9.8% (17 of 173 patients) in the placebo group (risk ratio, 0.29; 95% confidence interval [CI], 0.11-0.74, P = 0.0073). The incidence rates of bacteremia were 2.3% (4 of 176 patients) and 6.4% (11 of 173 patients), respectively (risk ratio, 0.36; 95% CI, 0.12-1.04; P = 0.0599). The incidence rate of cholangitis was 1.7% (3 of 176 patients) in the antibiotic prophylaxis group and 6.4% (11 of 173 patients) in the placebo group (risk ratio, 0.27; 95% CI, 0.08-0.87; P = 0.0267). DISCUSSION: Antibiotic prophylaxis before ERCP in patients with biliary obstruction resulted in a significantly lower risk of infectious complications, especially cholangitis, than placebo ( ClinicalTrials.gov trial number NCT02958059).

Transgelin-2, a novel cancer stem cell-related biomarker, is a diagnostic and therapeutic target for biliary tract cancer.

BACKGROUND: Biliary tract cancer (BTC) is a relatively rare but aggressive gastrointestinal cancer with a high mortality rate. Cancer stem cell (CSC) populations play crucial roles in tumor biology and are responsible for the low response to anti-cancer treatment and the high recurrence rate. This study investigated the role of Transgelin-2 (TAGLN2), overexpressed in CSC in BTC cells, and analyzed its expression in patient tissues and serum to identify potential new targets for BTC. METHODS: TAGLN2 expression was suppressed by small-interfering or short hairpin RNAs, and its effects on tumor biology were assessed in several BTC cell lines. Furthermore, the effects of TAGLN2 silencing on gemcitabine-resistant BTC cells, differentially expressed genes, proteins, and sensitivity to therapeutics or radiation were assessed. TAGLN2 expression was also assessed using western blotting and immunohistochemistry in samples obtained from patients with BTC to validate its clinical application. RESULTS: Suppression of TAGLN2 in BTC cell lines decreased cell proliferation, migration, invasion, and tumor size, in addition to a reduction in CSC features, including clonogenicity, radioresistance, and chemoresistance. TAGLN2 was highly expressed in BTC tissues, especially in cancer-associated fibroblasts in the stroma. Patients with a low stromal immunohistochemical index had prolonged disease-free survival compared to those with a high stromal immunohistochemical index (11.5 vs. 7.4 months, P = 0.013). TAGLN2 expression was higher in the plasma of patients with BTC than that in those with benign diseases. TAGLN2 had a higher area under the curve (0.901) than CA19-9, a validated tumor biomarker (0.799; P < 0.001). CONCLUSION: TAGLN2 plays a critical role in promoting BTC cell growth and motility and is involved in regulating BTC stemness. Silencing TAGLN2 expression enhanced cell sensitivity to radiation and chemotherapeutic drugs. The expression of TAGLN2 in patient tissue and plasma suggests its potential to serve as a secretory biomarker for BTC. Overall, targeting TAGLN2 could be an appropriate therapeutic strategy against advanced cancer following chemotherapy failure.

Covered versus uncovered double bare self-expandable metal stent for palliation of unresectable extrahepatic malignant biliary obstruction: a randomized controlled multicenter trial.

BACKGROUND AND AIMS: In a recent randomized controlled trial, a double bare metal stent (DBS) showed better stent patency than single-layer metal stents. However, clear evidence comparing the efficacy of uncovered (UCDBS) and partially covered (PCDBS) DBSs for distal malignant biliary obstruction (MBO) is lacking. Therefore, we compared the clinical outcomes including stent patency of UCDBSs versus PCDBSs. METHODS: A multicenter, randomized study was performed in patients with distal MBO. The primary endpoint was stent patency. Secondary endpoints were the proportion of patients with patent stents at 6 months, risk factors for stent dysfunction, overall survival, technical and clinical success rates of stent placement, and other adverse events (AEs). RESULTS: Among 258 included patients, 130 were randomly assigned to the PCDBS group and 128 to the UCDBS group. The mean duration of stent patency of the PCDBS (421.2 days; 95% confidence interval [CI], 346.7-495.7) was longer than that of the UCDBS (377.4 days; 95% CI, 299.7-455.0), although total stent dysfunction and stent dysfunction within 6 months were not different between groups. Multivariate analysis indicated that chemotherapy after stent placement was a significant factor for overall survival (hazard ratio, .570; 95% CI, .408-.796) and had a marginal impact on stent patency (hazard ratio, 1.569; 95% CI, .923-2.667). There were no remarkable differences in AEs, including pancreatitis, cholecystitis, and stent migration, between the 2 groups. CONCLUSIONS: The use of PCDBSs compared with UCDBSs in patients with distal MBO has unclear benefits regarding stent patency and overall survival, although PCDBSs have a lower rate of tumor ingrowth. (Clinical trial registration number: NCT02937246.).

Implant Removal After Medial Opening Wedge High Tibial Osteotomy Provides Implant-Related Pain Relief and Functional Improvement.

PURPOSE: To (1) investigate the incidence of implant-related pain after medial opening wedge high tibial osteotomy (MOWHTO) using a locking plate, (2) determine whether implant removal provides pain relief and functional improvement, and (3) evaluate bone healing and loss of correction after implant removal. METHODS: Between March 2014 and September 2017, MOWHTO was performed without bone graft. The inclusion criteria were patients who underwent implant removal after MOWHTO and were followed up for a minimum of 2 years. Patients were evaluated for implant removal 1 and 2 years after surgery. Clinical and functional evaluations were conducted to investigate implant-related pain using the visual analog scale, Lysholm score, and Tegner score. The radiographic indices measured were the gap-filling rate, weightbearing line (WBL) ratio, hip-knee-ankle angle (HKAA), medial proximal tibial angle (MPTA), and posterior tibial slope angle (PTSA). RESULTS: A total of 55 patients were enrolled. Fifty-one (92.7%) patients experienced implant-related pain prior to implant removal, with 43 and 8 patients reporting mild pain and moderate pain, respectively. At 1 and 2 years after implant removal, mild pain occurred in 6 (10.9%) and 5 (9.1%) patients, respectively. The remaining patients reported no implant-related pain. Prior to implant removal and 1 year after implant removal, the Lysholm score improved from 77.0 ± 5.6 to 86.8 ± 5.7 (P < .001), and the Tegner score improved from 3.3 ± 1.2 to 3.9 ± 1.3 (P < .001). The mean gap-filling rate was 84.4% ± 9.6% at implant removal, and it significantly increased to 93.7% ± 5.4% and 97.4% ± 2.6% at 1 and 2 years after implant removal, respectively (P < .001). For the WBL ratio, HKAA, MPTA, and PTSA, no statistically significant differences were found after implant removal. CONCLUSIONS: The incidence of implant-related pain after MOWHTO using the medial proximal tibial locking plate was high. Implant removal provides pain relief and functional improvement (met minimal clinically important differences). Even after implant removal, bone healing progressed gradually without a loss of correction in all patients. LEVEL OF EVIDENCE: Level IV, case series.

Low-salt diet increases mRNA expression of aldosterone-regulated transporters in the intermediate portion of the endolymphatic sac.

The endolymphatic sac is a small sac-shaped organ at the end of the membranous labyrinth of the inner ear. The endolymphatic sac absorbs the endolymph, in which the ion balance is crucial for inner ear homeostasis. Of the three sections of the endolymphatic sac, the intermediate portion is the center of endolymph absorption, particularly sodium transport, and is thought to be regulated by aldosterone. Disorders of the endolymphatic sac may cause an excess of endolymph (endolymphatic hydrops), a histological observation in Meniere's disease. A low-salt diet is an effective treatment for Meniere's disease, and is based on the assumption that the absorption of endolymph in the endolymphatic sac abates endolymphatic hydrops through a physiological increase in aldosterone level. However, the molecular basis of endolymph absorption in each portion of the endolymphatic sac is largely unknown because of difficulties in gene expression analysis, resulting from its small size and intricate structure. The present study combined reverse transcription-quantitative polymerase chain reaction and laser capture microdissection techniques to analyze the difference of gene expression of the aldosterone-controlled epithelial Na+ channel, thiazide-sensitive Na+-Cl- cotransporter, and Na+, K+-ATPase genes in the three individual portions of the endolymphatic sac in a rat model. A low-salt diet increased the expression of aldosterone-controlled ion transporters, particularly in the intermediate portion of the endolymphatic sac. Our findings will contribute to the understanding of the physiological function of the endolymphatic sac and the pathophysiology of Meniere's disease.

A phase I/II study of ivaltinostat combined with gemcitabine and erlotinib in patients with untreated locally advanced or metastatic pancreatic adenocarcinoma.

This phase I/II study evaluated the safety and efficacy of a new histone deacetylase (HDAC) inhibitor, ivaltinostat, in combination with gemcitabine and erlotinib for advanced pancreatic ductal adenocarcinoma (PDAC). Patients diagnosed with unresectable, histologically confirmed PDAC who had not undergone previous therapy were eligible. Phase I had a 3 + 3 dose escalation design to determine the maximum tolerable dose (MTD) of ivaltinostat (intravenously on days 1, 8 and 15) with gemcitabine (1000 mg/m2 intravenously on days 1, 8 and 15) and erlotinib (100 mg/day, orally) for a 28-day cycle. In phase II, patients received a six-cycle treatment with the MTD of ivaltinostat determined in phase I. The primary endpoint was the objective response rate (ORR). Secondary endpoints included overall survival (OS), disease control rate (DCR) and progression-free survival (PFS). The MTD of ivaltinostat for the phase II trial was determined to be 250 mg/m2 . In phase II, 24 patients were enrolled. The median OS and PFS were 8.6 (95% confidence interval [CI]: 5.3-11.2) and 5.3 months (95% CI: 3.7-5.8). Of the 16 patients evaluated for response, ORR and DCR were 25.0% and 93.8% with a median OS/PFS of 10.8 (95% CI: 8.3-16.7)/5.8 (95% CI: 4.6-6.7) months. Correlative studies showed that mutation burden detected by cfDNA and specific blood markers such as TIMP1, pro-MMP10, PECAM1, proMMP-2 and IGFBP1 were associated with clinical outcomes. Although the result of a small study, a combination of ivaltinostat, gemcitabine and erlotinib appeared to be a potential treatment option for advanced PDAC.

Effects of modified trans-tibial versus trans-portal technique on stress patterns around the femoral tunnel in anatomical single-bundle ACL reconstruction with different knee flexion angles using finite element analysis.

BACKGROUND: It is unclear whether different anterior cruciate ligament (ACL) graft trajectories in the distal femur would have different effects on stress generated within the distal femur around the femoral tunnel during knee motion. Thus, the purpose of this study was to determine differences in stress patterns around the femoral tunnel created by trans-portal (TP) vs. modified trans-tibial (TT) technique in anatomical ACL reconstruction at different knee flexion angles. METHODS: Twelve male subjects' right knees were scanned with a high-resolution computed tomography (CT) scanner (slice thickness: 1 mm) at four different knee flexion angles (0°, 45°, 90°, and 135°). Three-dimensional (3D) models of these four different flexion angles were created and manipulated with several modelling programs. For the TP group, the virtual femoral tunnelling procedure was performed in a 135° flexion model from the low far anteromedial (AM) portal. For the modified TT group, the same knee models were drilled through the modified TT technique at 90° of flexion separately. Virtual grafts under tension of 40 N were put into corresponding bone tunnel and fixed at the outer aperture of femoral tunnels to simulate the suspensory fixation, followed by fixation of the grafts at the middle of tibial tunnels in the 0° knee flexion models. Finally, the models were exported to a finite element analysis package and analysed using ABAQUS/Explicit code (ABAQUS, USA) to monitor the stress occurring at the node where stress distribution occurred most significantly in the femoral bone around the bone tunnel. RESULTS: In general, both groups showed a high stress distribution in bony structures around inner and outer orifices of the femoral tunnel. Mean maximal stresses occurring at the lateral femoral condyle around the inner orifice of the femoral tunnel in the TP group were found to be significantly greater than those in the modified TT group at all flexion angles except 90° of flexion. Mean maximal stresses monitored around the outer orifice of the femoral tunnel in the TP group were also significantly greater than those in the modified TT group at all flexion angles. CONCLUSIONS: Different tunnelling technologies could yield different stress patterns in the lateral femoral condyle around the femoral tunnel. During knee motion, higher stresses were noticed in the TP group than in the modified TT group, especially around inner and outer orifices of the tunnel. Position of the tunnel after reconstruction with the TP technique can have a greater effect on the stress increase in the femur compared to that with the modified TT technique.

Bone healing on serial plain radiographs occurs slowly but adequately after medial opening wedge high tibial osteotomy without bone graft.

PURPOSE: The purpose of this study was to prospectively investigate osteotomy gap filling rates on serial plain radiographs, and to evaluate whether alignment correction is maintained after medial opening wedge high tibial osteotomy (MOWHTO) using a locking plate without bone graft. METHODS: Between March 2014 and June 2017, MOWHTO was performed without bone graft regardless of gap size. Radiographs were taken preoperatively, postoperatively, at 1, 3, 6, 12, 18, and 24 months after surgery. Radiographic examinations included a weight bearing long-standing anteroposterior (AP) view of the whole lower extremity, as well as, the AP, lateral, and both oblique views of the knee. Bone healing was measured on the medial oblique view of the knee. The postoperative alignment correction and its maintenance were assessed using the three radiologic parameters of the weight-bearing line (WBL) ratio, the hip-knee-ankle angle (HKAA), and the medial proximal tibial angle (MPTA) on the weight-bearing long-standing AP view of the lower extremity. RESULTS: Fifty-two consecutive patients underwent MOWHTO, but three patients failed to follow-up for more than 24 months. A total of 49 patients were assessed in this study. The median opening gap height was 10.0 mm (IQR, 8.0-12.0; range, 7-20). On immediate post-operative radiographs, the mean gap filling was 31.4 ± 3.6%. After 1, 3, 6, 12, 18, and 24 months, the mean gap filling rates increased to 38.7 ± 4.4%, 51.4 ± 6.6%, 66.5 ± 5.1%, 84.8 ± 7.0%, 92.4 ± 5.6%, and 97.8 ± 2.3%, respectively. Statistical differences were observed between all the follow-up evaluations (P < 0.001). Statistical differences in the WBL ratio, HKAA, and MPTA were observed between preoperatively and 1 month after surgery (P < 0.001). The mean PTSA increased significantly from preoperatively to postoperatively (P < 0.001). However, no statistical differences were found between the post-operative follow-up radiographs performed for these four values. CONCLUSION: MOWHTO using a locking plate without bone graft achieved at least 90% bone healing and had no loss in correction at 2 years postoperatively. LEVEL OF EVIDENCE: III.

GLRX3, a novel cancer stem cell-related secretory biomarker of pancreatic ductal adenocarcinoma.

BACKGROUND: Cancer stem cells (CSCs) are implicated in carcinogenesis, cancer progression, and recurrence. Several biomarkers have been described for pancreatic ductal adenocarcinoma (PDAC) CSCs; however, their function and mechanism remain unclear. METHOD: In this study, secretome analysis was performed in pancreatic CSC-enriched spheres and control adherent cells for biomarker discovery. Glutaredoxin3 (GLRX3), a novel candidate upregulated in spheres, was evaluated for its function and clinical implication. RESULTS: PDAC CSC populations, cell lines, patient tissues, and blood samples demonstrated GLRX3 overexpression. In contrast, GLRX3 silencing decreased the in vitro proliferation, migration, clonogenicity, and sphere formation of cells. GLRX3 knockdown also reduced tumor formation and growth in vivo. GLRX3 was found to regulate Met/PI3K/AKT signaling and stemness-related molecules. ELISA results indicated GLRX3 overexpression in the serum of patients with PDAC compared to that in healthy controls. The sensitivity and specificity of GLRX3 for PDAC diagnosis were 80.0 and 100%, respectively. When GLRX3 and CA19-9 were combined, sensitivity was significantly increased to 98.3% compared to that with GLRX3 or CA19-9 alone. High GLRX3 expression was also associated with poor disease-free survival in patients receiving curative surgery. CONCLUSION: Overall, these results indicate GLRX3 as a novel diagnostic marker and therapeutic target for PDAC targeting CSCs.

Peripheral natural killer cell activity is associated with poor clinical outcomes in pancreatic ductal adenocarcinoma.

BACKGROUND AND AIM: We aimed to measure the natural killer (NK) cell activity and pro-inflammatory cytokine levels in the peripheral blood of pancreatic cancer patients and investigate the correlation of NK cell activity and cytokines with cancer status and clinical outcomes. METHODS: We prospectively enrolled patients who were pathologically diagnosed with pancreatic ductal adenocarcinoma (PDAC) between 2016 and 2017 at a tertiary hospital in Seoul, South Korea. As a control group, healthy participants were enrolled by mobile application recruitment. RESULTS: A total of 203 patients were enrolled for this study (PDAC, n = 102; healthy participants, n = 101). The peripheral blood NK cell activity of PDAC patients was significantly lower than that of healthy participants (median level, 95 pg/mL vs 2000 pg/mL, P < 0.001), and decreased NK cell activity was correlated to poor clinical outcome in terms of response to chemotherapy, tumor progression, and survival. The pro-inflammatory cytokine interleukin-6 had a strong negative correlation with NK cell activity. CONCLUSIONS: In pancreatic cancer patients, NK cell activity decreased as cancer progressed, and decreased NK cell activity was associated with poor clinical outcomes.

Efficacy and safety of palliative endobiliary radiofrequency ablation using a novel temperature-controlled catheter for malignant biliary stricture: a single-center prospective randomized phase II TRIAL.

BACKGROUND: Endobiliary radiofrequency ablation (EB-RFA) has emerged as a palliative treatment for malignant biliary strictures (MBSs); however, concerns about complications related to thermal injury remain. In this study, we evaluated the efficacy and safety of EB-RFA with a novel catheter for MBS. METHODS: Patients with inoperable cancer causing MBS were randomly assigned to either the radiofrequency ablation (RFA) group or the non-RFA group. The RFA group underwent EB-RFA at the stricture site with a temperature-controlled catheter (ELRA™; STARmed Co., Goyang, Korea) followed by deployment of a self-expanding metal stent (SEMS). For the non-RFA group, only SEMS placement was performed. The duration of stent patency, overall survival (OS), and 30-day complication rate were evaluated. This trial was registered at ClinicalTrials.gov (number NCT02646514). RESULTS: A total of 48 patients were enrolled (24 in each group). During a median follow-up period of 135.0 days (RFA group) and 119.5 days (non-RFA group), the 90-day stent patency rate, median duration of stent patency, and median OS were not different between the groups (58.3% vs. 45.8% [P = 0.386], 132.0 days vs. 116.0 days [P = 0.440], and 244.0 days vs. 180.0 days [P = 0.281], respectively). In the RFA group, procedure-related complications including thermal injury-related complications, such as bile duct perforation or hemobilia, were not reported. The early complication (< 7 days) rates were not different between the groups (4.2% vs. 12.5%, P = 0.609), and there were no late complications (7-30 days) in both groups. CONCLUSION: EB-RFA with a temperature-controlled catheter followed by SEMS placement for patients with inoperable MBS can be safe and feasible with acceptable biliary patency.

Optimal drainage of anastomosis stricture after living donor liver transplantation.

BACKGROUND: Endoscopic biliary stenting (EBS) with a fully covered, self-expandable metallic stent (FC-SEMS) and plastic stent (PS) is safe and efficient for biliary anastomotic strictures (ASs) after a deceased donor liver transplantation. Limited studies have investigated the use of FC-SEMSs for biliary strictures post-living donor liver transplantation (LDLT). We compared the resolution rate of biliary ASs post-LDLT and the 12-month recurrence rates post-stent removal between EBS with an FC-SEMS, PS, and percutaneous transhepatic biliary drainage (PTBD). METHODS: Patients with biliary ASs after an LDLT (mean age: 57.3 years, 76.1% men) hospitalized between 2014 and 2017 were enrolled. Endoscopic retrograde cholangiopancreatography (ERCP) was repeated every 3-4 months. Patients were followed-up for at least 1-year post-stent removal. RESULTS: Of the 75 patients enrolled, 16, 20, and 39 underwent EBS with an FC-SEMS, PS, and PTBD, respectively. Median follow-up period was 39.2 months. Fewer ERCP procedures were needed in the FC-SEMS group than in the PS group (median, 2 vs. 3; P = 0.20). Median stent indwelling periods were 4.7, 9.3, and 5.4 months in the FC-SEMS, PS, and PTBD groups, respectively (P = 0.006). The functional resolution rate was lower in the PS group (16/20) than in the FC-SEMS (16/16) or PTBD (39/39) group (P = 0.005). The radiologic resolution rate was higher in the FC-SEMS group (16/16) than in the PS group (14/20) (P = 0.07). The 12-month recurrence rates showed no significant differences (FC-SEMS, 4/16; PS, 3/16; PTBD, 6/39; P = 0.66). The rates of complications during treatment differed significantly between the groups (P = 0.04). Stent migration occurred in 1 (6.3%) and 5 (25.0%) patients in the FC-SEMS and PS groups, respectively (P = 0.59). CONCLUSIONS: EBS with an FC-SEMS is comparable with EBS with a PS or PTBD in terms of biliary stricture resolution and 12-month recurrence rates. The use of FC-SEMSs is potentially effective and safe for biliary AS resolution after LDLT.

Lesion Size May Predict Return to Play in Young Elite Athletes Undergoing Microfracture for Osteochondral Lesions of the Talus.

PURPOSE: To evaluate the clinical and sports-related outcomes of arthroscopic microfracture (MFx) for osteochondral lesion of the talus (OLT) in elite athletes. METHODS: The athletes who underwent arthroscopic MFx for OLTs at our institution between January 2011 and September 2015 with minimum 2 years of follow-up were reviewed. The Foot and Ankle Outcome Score, American Orthopaedic Foot & Ankle Society, and visual analog scale pain score, time and rate of "return-to-competition" (RTC, return to an official match for at least 1 minute after treatment), and rate of "return-to-play" (RTP, participation in at least 2 entire seasons after treatment) were used to evaluate the outcomes. We compared athletes who were able to RTP with those who were not. RESULTS: In total, 41 patients (mean age 19.34 ± 3.76 years) were included. The mean follow-up was 54.9 ± 13.72 months. In total, 36 patients had medial lesions, and 5 patients had lateral lesions. All subscales of preoperative Foot and Ankle Outcome Score were significantly improved at the final follow-up. The mean preoperative American Orthopaedic Foot & Ankle Society score of 74.46 ± 8.10 improved to 91.62 ± 2.99 (P < .001) at the final follow-up. The mean preoperative visual analog scale pain score of 5.44 ± 1.57 improved to 2.66 ± 1.04 (P < .001). All patients achieved RTC (100%) at mean time of 5.45 ± 3.18 months, and 74.4% of patients were able to RTP. The RTP-group showed significantly smaller lesions compared to the No-RTP group (71.52 ± 43.29 vs 107.00 ± 45.28 mm2, P = .009). The cut-off OLT size for predicting RTP was 84.0 mm2, with a sensitivity of 90.0% and specificity of 75.9%. CONCLUSIONS: All athletes were able to RTC at average of 5.45 months after MFx for OLTs with minimal subchondral involvement, and 74.4% were able to RTP. The only prognostic variable for RTP was lesion size, and its predictive cut-off was 84.0 mm2. LEVEL OF EVIDENCE: IV, Case series.

Identification of Circulating Serum miRNAs as Novel Biomarkers in Pancreatic Cancer Using a Penalized Algorithm.

Pancreatic cancer (PC) is difficult to detect in the early stages; thus, identifying specific and sensitive biomarkers for PC diagnosis is crucial, especially in the case of early-stage tumors. Circulating microRNAs are promising non-invasive biomarkers. Therefore, we aimed to identify non-invasive miRNA biomarkers and build a model for PC diagnosis. For the training model, blood serum samples from 63 PC patients and 63 control subjects were used. We selected 39 miRNA markers using a smoothly clipped absolute deviation-based penalized support vector machine and built a PC diagnosis model. From the double cross-validation, the average test AUC was 0.98. We validated the diagnosis model using independent samples from 25 PC patients and 81 patients with intrahepatic cholangiocarcinoma (ICC) and compared the results with those obtained from the diagnosis using carbohydrate antigen 19-9. For the markers miR-155-5p, miR-4284, miR-346, miR-7145-5p, miR-5100, miR-661, miR-22-3p, miR-4486, let-7b-5p, and miR-4703-5p, we conducted quantitative reverse transcription PCR using samples from 17 independent PC patients, 8 ICC patients, and 8 healthy individuals. Differential expression was observed in samples from PC patients. The diagnosis model based on the identified markers showed high sensitivity and specificity for PC detection and is potentially useful for early PC diagnosis.

Risk of a complete exchange or failure in total knee arthroplasty and unicompartmental knee arthroplasty: a nationwide population-based cohort study from South Korea.

PURPOSE: Few large-scale studies using adjusted data from national registries have explored the risk factors of subsequent revision in patients with unicompartmental knee arthroplasty (UKA) compared to those with total knee arthroplasty (TKA). We investigated the incidence rate and risk factors of subsequent revision in patients with UKA and TKA. METHODS: We enrolled all patients who had undergone TKA or UKA as the primary surgical procedure without histories of having undergone either procedure during the preceding 2 years. Matched Cox regression models were used to compare the risks of revision between groups after propensity score matching. Revision was defined as conversion to revision TKA after primary TKA and conversion to TKA after UKA. RESULTS: The study enrolled 418,806 TKA patients and 446,009 UKA patients. The risk of revision during the entire study period was higher for patients with UKA than for patients with TKA (adjusted hazard ratio [HR] 1.22, 95% confidence interval [95% CI]: 1.10-1.36). The Kaplan-Meier 8-year survival was 98.7% in the TKA group and 96.7% in the UKA group. Patients with UKA were at an increased risk of revision in cases of advanced age (70-79 years, HR 1.40, 95% CI: 1.15-1.71), female sex (HR 1.32, 95% CI: 1.16-1.49), the presence of chronic obstructive pulmonary disease (COPD) (HR 1.27, 95% CI: 1.05-1.54), the presence of peptic ulcer disease (PUD) (HR 1.34, 95% CI: 1.11-1.61) compared to patients with TKA. In patients with hemiplegia, however, UKA were associated with a lower risk of subsequent revision (HR 0.25, 95% CI: 0.07-0.94). CONCLUSION: The risk of a complete exchange or failure was higher for patients with UKA than for patients with TKA. The most significant independent risk factors for subsequent a complete exchange or failure in patients with UKA were advanced age (70-79 years), female sex, and the presence of comorbidities such as COPD and PUD.

Radiographic portal or superior mesenteric vein invasion is an independent prognostic factor in non-metastatic pancreatic ductal adenocarcinoma: A missing block of clinical T staging?

BACKGROUND: Venous invasion is not included in the pancreatic ductal adenocarcinoma (PDAC) staging, and its correlation with prognosis remains unclear. We evaluated the prognostic impact of radiographic portal/superior mesenteric vein (PV/SMV) invasion, and its possibility of complementing T staging. METHODS: We identified patients with non-metastatic PDAC using our institutional cohort, and divided them according to PV/SMV invasion at imaging, defined as >180-degree tumor-vessel interface or contour deformity. We conducted Cox proportional hazard regression, and compared survival in the original and 1:1 propensity score matched datasets. RESULTS: We identified 454 patients [PV/SMV(+): 172; PV/SMV(-): 282]. In the multivariate analysis, PV/SMV invasion, age (≥70 years), performance status, tumor size (2-4, >4 cm), lymph nodes >4, and arterial invasion was correlated with prognosis. The PV/SMV(+) group had a shorter overall survival (OS) than the PV/SMV(-) group in the original (14.4 vs. 20.9 months; P < 0.001) and matched datasets (14.3 vs. 17.2 months; P = 0.009). Among patients without arterial invasion (cT1-cT3), the PV/SMV(+) group had a shorter OS (15.9 vs. 21.2 months; P = 0.002). Moreover, their OS did not differ from that of patients with arterial invasion (cT4) (15.9 vs. 14.4 months; P = 0.907). Patients with vessel (artery/vein) invasion had a shorter OS than those without vessel invasion (14.5 vs. 21.2 months; P < 0.001). CONCLUSIONS: Radiographic PV/SMV invasion in non-metastatic PDAC was correlated with a poor prognosis. It could identify a group with shorter OS among patients without arterial invasion (cT1-cT3). It is suggested that inclusion of PV/SMV invasion in clinical T4 criteria should be considered.

Preoperative prediction of futile surgery in patients with radiologically resectable or borderline resectable pancreatic adenocarcinoma.

BACKGROUND AND AIM: The aim of this study is to identify the predictive factors for futile surgery in patients with radiologically resectable or borderline resectable pancreatic cancer and to develop a prediction model. METHODS: This retrospective study included patients who underwent pancreatic surgery for pancreatic cancer between 2006 and 2017. To identify independent risk factors for futile surgery, logistic regression and random forest analyses were performed in the training cohort, based on which a nomogram was established. The predictive accuracy and discriminative ability of the nomogram were validated in the validation cohort. RESULTS: Of 389 patients who underwent pancreatic surgery, the laparotomy was futile in 40 patients (10.3%). In the training cohort, the univariate and multivariate logistic regression analyses revealed that serum carbohydrate antigen 19-9 level of ≥ 150 U/mL (P = 0.003), the presence of suspicious lymph node (P = 0.013), and more extensive peripancreatic tumor infiltration (P < 0.001) were independent predictive factors for futile surgery. The bootstrap-corrected concordance index of the nomogram was high in the training cohort, 0.826 with a 95% confidence interval of 0.745-0.907. This model also showed a good discriminative performance in the validation cohort, with a concordance index of 0.831. CONCLUSIONS: We established and validated a novel nomogram that predicts the risk of futile surgery due to occult distant metastasis in patients with radiologically resectable or borderline resectable pancreatic cancer.

Initial conservative treatment of osteochondral fracture of the patella following first-time patellar dislocation.

BACKGROUND: There has been no gold standard of the initial treatment strategy for acute patellar dislocation (APD) with osteochondral fracture (OCF). Hence the study aim is firstly, to review and compare clinical outcomes of patients who underwent conservative treatment for APD with or without OCF. Secondly, to characterize the location and size of fracture fragment. METHODS: Sixty-nine consecutive patients who were retrospectively evaluated after first-time APD over a 2- year period were divided into two groups (group 1 (n = 24): APD with OCF and group 2 (n = 45): APD only). Magnetic resonance imaging (MRI) was used to assess patients with APD and OCF from the medial patella. All patients were treated with a supervised course of immobilization followed by progressive range of motion and strength exercise protocol. History of a recurrent dislocation, radiologic and functional scores were analyzed. RESULTS: Redislocation rate was 31.2% in group 1 and 26.6% in group 2, showing no significant difference between the two groups (p = 0.690). Intergroup differences in terms of final Kujala and IKDC scores were not significant (p = 0.117 and p = 0.283, respectively). Fracture sites of the patella in group 1 were classified as follows: patellar medial margin (12), inferomedial facet (7), and inferomedial facet involving central ridge (5). In the subgroup of patient with OCF of the inferomedial facet of the patella, the fragments were found in the lateral gutter and did not cause pain or mechanical symptoms. Thus, loose body removal was not performed. However, all five patients with large OCF involving the central ridge of the patella failed non-operative treatment with recurrent dislocations, ultimately requiring fragment refixation and medial retinacular imbrication. CONCLUSIONS: First, APD patients with OCFs of medial margin or inferomedial facet showed similar redislocation rates and functional knee scores with those without OCFs after conservative treatment. Second, initial conservative treatment failed in some APD patients with large OCF, especially when OCFs were fractured from inferomedial facet involving central ridge. Surgery should be considered with this type.