Closed reduction and internal fixation for tillaux fractures, based on pre-operative three-dimensional computed tomography.

OBJECTIVE: This study aimed to propose treatment protocol and identify patterns of tillaux fractures using three-dimensional (3D) computed tomography (CT) analysis and to describe an effective reduction technique. METHODS: Forty-two juvenile patients with tillaux fractures were evaluated with 3D-CT scan for fracture displacement pattern and received surgical treatment. Tillaux fragment was reduced by pushing the superomedial quadrant part of the fragment slightly downward towards the ankle joint from anterolateral to posteromedial through 5-mm skin incisions with mosquito forceps. A 4.0 cannulated screw was subsequently inserted from the anterolateral to the posteromedial side parallel to the ankle joint. We analysed the distance and direction of fracture displacement with 3D-CT before the surgery. Pre-operative and post-operative plain radiographs were evaluated. RESULTS: Pre-operative 3D-CT analysis revealed a common fracture pattern, varus tilt, and external rotation of fragment. We achieved satisfactory reduction with residual fracture gaps less than 2 mm in 42 cases. Two cases had a 13-mm anterior gap that was reduced by mini-open reduction because of periosteal impingement. No significant clinical complications were found. CONCLUSION: The closed reduction technique developed based on the fracture pattern identified by 3D-CT anatomical analysis is safe and effective in treating tillaux fractures.

Mucosal TLR5 activation controls healthspan and longevity.

Addressing age-related immunological defects through therapeutic interventions is essential for healthy aging, as the immune system plays a crucial role in controlling infections, malignancies, and in supporting tissue homeostasis and repair. In our study, we show that stimulating toll-like receptor 5 (TLR5) via mucosal delivery of a flagellin-containing fusion protein effectively extends the lifespan and enhances the healthspan of mice of both sexes. This enhancement in healthspan is evidenced by diminished hair loss and ocular lens opacity, increased bone mineral density, improved stem cell activity, delayed thymic involution, heightened cognitive capacity, and the prevention of pulmonary lung fibrosis. Additionally, this fusion protein boosts intestinal mucosal integrity by augmenting the surface expression of TLR5 in a certain subset of dendritic cells and increasing interleukin-22 (IL-22) secretion. In this work, we present observations that underscore the benefits of TLR5-dependent stimulation in the mucosal compartment, suggesting a viable strategy for enhancing longevity and healthspan.

A Novel Model for Predicting the Sagittal Length of the Distal Tibia Using CT Imaging and Statistics.

The purpose of this study was to determine the ratio of sagittal length to coronal length of the distal tibia for predicting the sagittal length of the distal tibia. A total of 202 ankles were measured based on CT imaging availability. We measured the coronal length (Width, W) parallel to the Chaput tubercle from CT scans. Sagittal length was divided into 3 points (Diameter D1, D2, D3) in the axial plane on the same level. The relationship between coronal length and each sagittal length was determined through correlation analysis. A prediction model was then developed using multiple regression. We also analyzed the quality of the prediction model and validated the prediction model with a validation cohort. Each sagittal length (D1, D2, D3) and coronal length had a significant positive correlation (p < .01). In the prediction model, sex, height, and W were significantly associated with D1, D2, and D3 (p < .05). Prediction models were made for each sagittal length (D1, D2, D3). Concordance correlation coefficient (CCC) values of prediction models for D1, D2, and D3 were 0.78, 0.72, and 0.72 for the derivation cohort and 0.69, 0.63, and 0.61 for the validation cohort, respectively. Accuracies of models as ± 2SD for D1, D2, and D3 were 93.9%, 94.9%, and 94.9%, respectively. This study predicted the sagittal length of the distal tibia for preoperative planning by measuring the coronal length of the distal tibia. Prediction of the sagittal length of the distal tibia can help foot and ankle surgeons fixate screws stably to prevent iatrogenic injury of posterior structures of the distal tibia.

CD5 Expression Dynamically Changes During the Differentiation of Human CD8+ T Cells Predicting Clinical Response to Immunotherapy.

Defining the molecular dynamics associated with T cell differentiation enhances our understanding of T cell biology and opens up new possibilities for clinical implications. In this study, we investigated the dynamics of CD5 expression in CD8+ T cell differentiation and explored its potential clinical uses. Using PBMCs from 29 healthy donors, we observed a stepwise decrease in CD5 expression as CD8+ T cells progressed through the differentiation stages. Interestingly, we found that CD5 expression was initially upregulated in response to T cell receptor stimulation, but diminished as the cells underwent proliferation, potentially explaining the differentiation-associated CD5 downregulation. Based on the proliferation-dependent downregulation of CD5, we hypothesized that relative CD5 expression could serve as a marker to distinguish the heterogeneous CD8+ T cell population based on their proliferation history. In support of this, we demonstrated that effector memory CD8+ T cells with higher CD5 expression exhibited phenotypic and functional characteristics resembling less differentiated cells compared to those with lower CD5 expression. Furthermore, in the retrospective analysis of PBMCs from 30 non-small cell lung cancer patients, we found that patients with higher CD5 expression in effector memory T cells displayed CD8+ T cells with a phenotype closer to the less differentiated cells, leading to favorable clinical outcomes in response to immune checkpoint inhibitor (ICI) therapy. These findings highlight the dynamics of CD5 expression as an indicator of CD8+ T cell differentiation status, and have implications for the development of predictive biomarker for ICI therapy.

Factors influencing successful bone union of isolated subtalar arthrodesis for posttraumatic subtalar arthritis: a multicenter case series.

BACKGROUND: The purpose of this study was to find the factors influencing successful bone union for isolated subtalar arthrodesis in posttraumatic subtalar arthritis following calcaneal fracture. MATERIAL AND METHODS: We retrospectively analyzed the rate of successful bone union of 119 cases of isolated subtalar arthrodesis for posttraumatic subtalar arthritis performed at five university hospitals between January 2010 and December 2019. Multivariate logistic regression analysis was used to find the factors associated with successful bone union. Successful bone union was defined as resolution of hindfoot pain with the presence of osseous trabecular bridging involving more than 50% of the posterior facet within 6 months postoperatively. RESULTS: There were 77 (64.7%) cases of successful bone union, 11 (9.2%) cases of delayed union, 8 (6.7%) cases of questionable union, and 23 (19.3%) cases of nonunion. Use of fully threaded screws was 5.90 times [odds ratio (OR) = 5.90, 95% confidence interval (CI) = 1.42-24.49, p = 0.02] more likely to achieve successful bone union compared to the use of partially threaded screws. Use of two parallel screws or the two divergent screws were 3.71 times (OR = 3.71, 95% CI = 1.05-13.14, p = 0.04) and 4.65 times (OR = 4.65, 95% CI = 1.23-17.53, p = 0.02) more likely to achieve successful bone union compared to the use of a single screw. Use of cancellous autograft or structural autograft was 4.72 times (OR = 4.72, 95% CI = 1.17-19.06, p = 0.03) and 7.12 times (OR = 7.12, 95% CI = 1.46-34.68, p = 0.02) more likely to achieve successful bone union compared to no graft use. CONCLUSION: Use of fully threaded screws, autograft, and two screws compared to a single screw were the factors associated with successful bone union within six postoperative months after subtalar arthrodesis for the posttraumatic arthritis.

Blood-Based Biomarker Analysis for Predicting Efficacy of Chemoradiotherapy and Durvalumab in Patients with Unresectable Stage III Non-Small Cell Lung Cancer.

We recruited 50 patients with unresectable stage III NSCLC who received CCRT between March 2020 and March 2021. Durvalumab consolidation (DC) was administered to patients (n = 23) without progression after CCRT and programmed death-ligand 1 (PD-L1) ≥ 1%. Blood samples were collected before (C0) and after CCRT (C1) to calculate PBC counts and analyze CTCs. CTCs, isolated by the CD-PRIMETM system, exhibited EpCAM/CK+/CD45- phenotype in BioViewCCBSTM. At median follow-up of 27.4 months, patients with residual CTC clusters at C1 had worse median PFS than those without a detectable CTC cluster (11.0 vs. 27.8 months, p = 0.032), and this trend was noted only in the DC group (p = 0.034). Patients with high platelets at C1 (PLThi, >252 × 103/µL) had worse median PFS than those with low platelets (PLTlo) (5.9 vs. 17.1 months, p < 0.001). In multivariable analysis, PLThi and residual CTC clusters at C1 were independent risk factors for PFS, and DC group with PLThi and residual CTC clusters at C1 showed the worst median PFS (2.6 months, HR 45.16, p = 0.001), even worse than that of the CCRT alone group with PLThi (5.9 months, HR 15.39, p = 0.001). The comprehensive analysis of CTCs and PBCs before and after CCRT revealed that the clearance of CTC clusters and platelet counts at C1 might be potential biomarkers for predicting survival.

Effect of outpatient physician involvement on the physician orders for life-sustaining treatment completed by hospitalists: a cross-sectional study.

BACKGROUND: Hospitalists are becoming increasingly involved in end-of-life (EOL) care decision making. They participate in the completion of physician orders for life-sustaining treatment (POLST) for patients who have not yet decided whether to proceed with life-sustaining treatment (LST) at the EOL. However, hospitalists are not physicians who have continuously treated patients in outpatient settings; hence, the continuity of care may be poor. We aimed to analyze the effect of outpatient physician involvement on the POLST completed by hospitalists. METHODS: A retrospective cohort study was conducted in patients aged 18 years or older treated by hospitalists who completed POLST at Seoul National University Bundang Hospital from February 2018 to March 2020. The clinical and sociodemographic data were obtained through a medical chart review, and the differences in the characteristics of POLST were analyzed depending on the status of outpatient physician involvement. RESULTS: A total of 3,533 POLST forms were written, of which 175 (5.22%) were completed by the hospitalists. The proportion of POLSTs completed by hospitalists gradually increased from 2.53% in 2018 to 4.58% in 2019 and 15.9% in 2020. A total of 144 (82.3%) patients had malignancies, while 31 (17.7%) patients had non-cancer illnesses. In 47.4% of the patients, outpatient physicians were involved in completing physician's orders for LST. When the outpatient physicians were involved, more patients signed the POLST form themselves (P=0.02) and chose comfort measures only when asked to determine their preferred LST type (P=0.00). CONCLUSIONS: The completion of POLST by hospitalists is gradually increasing. LST was reduced when the outpatient physicians participated in the completion of POLST. Using measures to increase the involvement of outpatient providers in goal care discussions, the quality and goal concordance of EOL care can be improved.

Second-look arthroscopic and magnetic resonance analysis after internal fixation of osteochondral lesions of the talus.

The purpose of this study was to evaluate cartilage quality after internal fixation of osteochondral lesion of the talus (OLT) using second-look arthroscopies and MRIs. Thirty-four patients underwent internal fixation of OLTs involving large bone fragments. Twenty-one of these patients underwent second-look arthroscopies and 23 patients underwent MRIs postoperatively. The arthroscopic findings were assessed using the International Cartilage Repair Society (ICRS) grading system, and the MRI findings were evaluated using the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. Five of the patients who underwent second-look arthroscopies showed normal cartilage, 12 showed nearly normal cartilage, 3 showed abnormal cartilage, and 1 showed severely abnormal cartilage, according to the overall ICRS repair grades. All the patients who achieved bone fragment union showed normal, or nearly normal cartilage upon second-look arthroscopy. The ICRS and MOCART scores were significantly higher for the patients with bone fragment union compared to those with nonunion (ICRS scores: 10.3 ± 1.5 vs. 6.0 ± 2.0, p < 0.001, MOCART score: 88.3 ± 10.0 vs. 39.0 ± 20.4, p < 0.001). Low signal intensities of the bone fragments on preoperative T1-weighted MRIs were not associated with nonunion (Fisher's exact test, p = 0.55), and the signal intensities increased postoperatively to levels similar to the underlying talus when bone union was achieved. Second-look arthroscopy and MRI showed normal, or nearly normal, cartilage after internal fixation of OLTs when bone union was achieved. The nonunion of bone fragments resulted in inferior cartilage quality.

Optimal management of recurrent and metastatic upper tract urothelial carcinoma: Implications of intensity modulated radiation therapy.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) is rare and the treatment for recurrent or metastatic UTUC is unclear. We evaluated the outcomes of salvage and palliative radiotherapy (RT) and prognostic factors in UTUC patients and find implications for salvage and palliative RT. METHODS: Between August 2006 and February 2021, 174 patients (median age, 68 years; range, 37-90) underwent salvage and palliative RT. Disease status at RT included initially diagnosed advanced disease (n = 8, 4.6%), local recurrence only (n = 56, 32.2%), distant metastasis only (n = 59, 33.9%), and local recurrence and distant metastasis (n = 51, 29.3%). The primary tumor location included the renal pelvis (n = 87, 50%), ureter (n = 77, 44.3%), and both (n = 10, 5.7%). Radical nephroureterectomy, chemotherapy, and immunotherapy were used in 135 (77.6%), 101 (58%), and 19 (10.9%) patients, respectively. Survival outcomes and prognostic factors were analysed using Cox and logistic regression analysis. RESULTS: Salvage RT and palliative RT was administered in 73 (42%) and 101 (58%) patients, respectively. The median radiation dose was 45 Gy (range, 15-65). Two-dimensional (2D) or three-dimensional (3D) RT and intensity modulated RT (IMRT) were used in 61 (35.1%) and 113 (64.9%) patients, respectively. The median follow-up was 7.8 months. The median duration of overall survival (OS) was 13.4 months, and the 1-year OS was 53.5%. The median progression-free survival (PFS) was 4.7 months, and the 6-month PFS was 41.9%. The 6-month infield PFS was 84%. In multivariate analysis, RT method (2D/3D vs. IMRT, p = 0.007) and RT response (p = 0.008) were independent prognostic factors for OS, and RT response correlated with PFS (p = 0.015). In subgroup analysis in patients with PD-L1 data, positive PD-L1 correlated with better PFS (p = 0.009). RT response-associated factors were concurrent chemotherapy (p = 0.03) and higher radiation dose (p = 0.034). Of 145 patients, 10 (6.9%) developed grade 3 acute or late toxicity. CONCLUSIONS: Salvage and palliative RT for UTUC are feasible and effective. Patients with RT response using IMRT may have survival benefit from salvage and palliative RT. Positive PD-L1 status might be related to radiosensitivity. High-dose radiation with concurrent chemotherapy may improve RT response.

Comparison of endoscopic treatments for small gastric adenomas.

BACKGROUND: Gastric adenomas can be successfully treated with endoscopic resection, including endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR). The aim of this study was to evaluate and compare the efficacy of ESD and EMR with circumferential precutting (EMR-P) in the treatment of small gastric adenomas. METHODS: This study included 1014 gastric adenomas ≤ 15 mm in diameter treated with ESD or EMR-P from 2012 to 2019, retrospectively. Propensity score matching between the ESD and EMR-P groups (1:1 to 3:1) was performed according to age, sex, tumor size, tumor location (upper, middle, and lower thirds), morphology, and preprocedural histology. The procedure time and the rates of en bloc resection, complete resection, adverse events, and local recurrence were compared between the two groups. RESULTS: After propensity score matching, 478 lesions (ESD: 295, EMR-P: 183) were analyzed. The rates of en bloc resection (94.9% vs. 93.4%, p = 0.498), complete resection (93.6% vs. 90.2%, p = 0.177), bleeding (8.1% vs. 3.8%, p = 0.063), and local recurrence (0.0% vs. 1.4%, p = 0.185) did not significantly differ between the two groups. The procedure time was significantly longer for ESD than for EMR-P (p < 0.001). In the EMR-P group, the complete resection rate was significantly lower in the upper third than in the middle and lower thirds (p < 0.001). CONCLUSION: EMR-P is as effective as ESD for the treatment of small gastric adenomas. However, the efficacy of EMR-P is lower for gastric adenomas in the proximal stomach.

Evolution of the Tumor Microenvironment toward Immune-Suppressive Seclusion during Brain Metastasis of Breast Cancer: Implications for Targeted Therapy.

Breast cancer (BC) is the second most common solid malignant tumor that metastasizes to the brain. Despite emerging therapies such as immunotherapy, whether the tumor microenvironment (TME) in breast cancer brain metastasis (BCBM) has potential as a target of new treatments is unclear. Expression profiling of 770 genes in 12 pairs of primary BC and matched brain metastasis (BM) samples was performed using the NanoString nCounter PanCancer IO360TM Panel. Immune cell profiles were validated by immunohistochemistry (IHC) in samples from 50 patients with BCBM. Pathway analysis revealed that immune-related pathways were downregulated. Immune cell profiling showed that CD8+ T cells and M1 macrophages were significantly decreased, and M2 macrophages were significantly increased, in BM compared to primary BC samples (p = 0.001, p = 0.021 and p = 0.007, respectively). CCL19 and CCL21, the top differentially expressed genes, were decreased significantly in BM compared to primary BC (p < 0.001, both). IHC showed that the CD8+ count was significantly lower (p = 0.027), and the CD163+ and CD206+ counts were higher, in BM than primary BC (p < 0.001, both). A low CD8+ T cell count, low CD86+ M1 macrophage count, and high M2/M1 macrophage ratio were related to unfavorable clinical outcomes. BC exhibits an immunosuppressive characteristic after metastasis to the brain. These findings will facilitate establishment of a treatment strategy for BCBM based on the TME of metastatic cancer.

CD8+ TILs in NSCLC differentiate into TEMRA via a bifurcated trajectory: deciphering immunogenicity of tumor antigens.

BACKGROUND: CD8+ tumor-infiltrating lymphocytes (TILs) comprise phenotypically and functionally heterogeneous subpopulations. Of these, effector memory CD45RA re-expressing CD8+ T cells (Temra) have been discovered and characterized as the most terminally differentiated subset. However, their exact ontogeny and physiological importance in association with tumor progression remain poorly understood. METHODS: We analyzed primary tumors and peripheral blood samples from 26 patients with non-small cell lung cancer and analyzed their phenotypes and functional characteristics using flow cytometry, RNA-sequencing, and bioinformatics. RESULTS: We found that tumor-infiltrating Temra (tilTemra) cells largely differ from peripheral blood Temra (pTemra), with distinct transcriptomes and functional properties. Notably, although majority of the pTemra was CD27-CD28- double-negative (DN), a large fraction of tilTemra population was CD27+CD28+ double-positive (DP), a characteristic of early-stage, less differentiated effector cells. Trajectory analysis revealed that CD8+ TILs undergo a divergent sequence of events for differentiation into either DP or DN tilTemra. Such a differentiation toward DP tilTemra relied on persistent expression of CD27 and CD28 and was associated with weak T cell receptor engagement. Thus, a higher proportion of DP Temra was correlated with lower immunogenicity of tumor antigens and consequently lower accumulation of CD8+ TILs. CONCLUSIONS: These data suggest a complex interplay between CD8+ T cells and tumors and define DP Temra as a unique subset of tumor-specific CD8+ TILs that are produced in patients with relatively low immunogenic cancer types, predicting immunogenicity of tumor antigens and CD8+ TIL counts, a reliable biomarker for successful cancer immunotherapy.

Early Weightbearing Versus Nonweightbearing After Operative Treatment of an Ankle Fracture: A Multicenter, Noninferiority, Randomized Controlled Trial.

BACKGROUND: Acute ankle fractures can occur during sports activities, and unstable ankle fractures are commonly treated operatively. However, controversy exists about the optimal time to allow weightbearing. HYPOTHESIS: Early weightbearing after the stable fixation of an ankle fracture is not inferior to nonweightbearing in terms of ankle function assessed at 12 months after injury. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 258 patients were assessed for eligibility. Of these patients, 194 were randomly allocated to either the early weightbearing group (95 patients who were allowed weightbearing at 2 weeks postoperatively) or the nonweightbearing group (99 patients who were not allowed weightbearing until 6 weeks postoperatively). The primary outcome measure was the mean difference in the Olerud-Molander ankle score (OMAS) between the groups, assessed at the 12-month follow-up examination. The secondary outcome measures were the time to return to preinjury activities and patients' subjective satisfaction. Complications such as hardware loosening or failure, fracture displacement, and nonunion were evaluated. RESULTS: The mean difference in the OMAS for the early weightbearing group compared with the nonweightbearing group was 1.6 (95% CI, -1.9 to 5.0) in the intention-to-treat analysis. The lower limit of the 95% CI (-1.9) exceeded the noninferiority margin of -8, indicating that early weightbearing was not inferior to nonweightbearing. The difference in the proportion of patients who were satisfied or very satisfied with their treatment was not statistically significant (84.3% vs 76.2%; P = .19); however, the time taken to return to preinjury activities was shorter with early weightbearing than with nonweightbearing (9.1 ± 3.0 vs 11.0 ± 3.0 weeks; P < .001). No cases of nonunion were observed in either group. CONCLUSION: Early weightbearing after the operative treatment of an unstable ankle fracture was not inferior to nonweightbearing in terms of OMAS assessed at 12 months after injury. The patients' subjective satisfaction was similar between the groups, although the time taken to return to preinjury activities was shorter in the early weightbearing group. REGISTRATION: NCT02029170 (ClinicalTrials.gov identifier).

Genetic Analysis Using a Next Generation Sequencing-Based Gene Panel in Patients With Skeletal Dysplasia: A Single-Center Experience.

Skeletal dysplasia (SD), a heterogeneous disease group with rare incidence and various clinical manifestations, is associated with multiple causative genes. For clinicians, accurate diagnosis of SD is clinically and genetically difficult. The development of next-generation sequencing (NGS) has substantially aided in the genetic diagnosis of SD. In this study, we conducted a targeted NGS of 437 genes - included in the nosology of SD published in 2019 - in 31 patients with a suspected SD. The clinical and genetic diagnoses were confirmed in 16 out of the 31 patients, and the diagnostic yield was 51.9%. In these patients, 18 pathogenic variants were found in 13 genes (COL2A1, MYH3, COMP, MATN3, CTSK, EBP, CLCN7, COL1A2, EXT1, TGFBR1, SMAD3, FIG4, and ARID1B), of which, four were novel variants. The diagnosis rate was very high in patients with a suspected familial SD and with radiological evidence indicating clinical SD (11 out of 15, 73.3%). In patients with skeletal involvement and other clinical manifestations including dysmorphism or multiple congenital anomalies, and various degrees of developmental delay/intellectual disability, the diagnosis rate was low (5 out of 16, 31.2%) but rare syndromic SD could be diagnosed. In conclusion, NGS-based gene panel sequencing can be helpful in diagnosing SD which has clinical and genetic heterogeneity. To increase the diagnostic yield of suspected SD patients, it is important to categorize patients based on the clinical features, family history, and radiographic evidence.

Hard-Soled Shoe Versus Short Leg Cast for a Fifth Metatarsal Base Avulsion Fracture: A Multicenter, Noninferiority, Randomized Controlled Trial.

BACKGROUND: The purpose of this study was to determine whether tolerated weight-bearing in a hard-soled shoe was noninferior to the use of a short leg cast for the treatment of a fifth metatarsal base avulsion fracture, as assessed with use of a 100-mm visual analog scale (VAS) for pain at 6 months after the fracture. METHODS: A total of 145 patients were assessed for eligibility. Of these, 96 patients were randomly assigned to either the hard-soled shoe group (46 patients) or the cast group (50 patients). The primary outcome measure was the mean difference on the 100-mm VAS between groups at 6 months after the fracture. Secondary outcome measures included the time to return to preinjury activity and patient-reported satisfaction. Analysis was performed according to both an intention-to-treat basis (i.e., patients were included in the assessment of their assigned treatment arm, even if they crossed over to the other treatment arm prior to completing the 6-month follow-up) and a per-protocol basis (i.e., patients who completed the 6-month follow-up were analyzed according to the treatment they received). RESULTS: At 6 months after the fracture, the mean 100-mm VAS was 8.6 ± 7.0 mm in the hard-soled shoe group and 9.8 ± 7.3 mm in the cast group (p = 0.41) according to intention-to-treat analysis. The mean difference in 100-mm VAS between the 2 groups was -1.3 mm (95% confidence interval, -4.3 to 1.8 mm). The upper limit of the 95% confidence interval did not exceed the noninferiority margin of 10 mm, indicating that treatment with the hard-soled shoe was noninferior to treatment with the short leg cast. The proportion of patients who reported satisfaction with their treatment was similar between the hard-soled shoe and cast groups (89.5% compared with 87.5%, respectively; p = 0.79), but the time to return to preinjury activity was significantly shorter in the hard-soled shoe group (37.2 ± 14.4 days compared with 43.0 ± 11.1 days in the cast group; p = 0.04). There were no cases of nonunion in either group. CONCLUSIONS: Weight-bearing as tolerated in a hard-soled shoe for a fifth metatarsal base avulsion fracture was noninferior to the use of a short leg cast as assessed with use of a 100-mm VAS at 6 months after the fracture. Patient-reported satisfaction was similar between groups, but the time to return to preinjury activity was shorter in the hard-soled shoe group. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Therapeutic effect of decellularized extracellular matrix-based hydrogel for radiation esophagitis by 3D printed esophageal stent.

Radiation esophagitis, the most common acute adverse effect of radiation therapy, leads to unwanted consequences including discomfort, pain, an even death. However, no direct cure exists for patients suffering from this condition, with the harmful effect of ingestion and acid reflux on the damaged esophageal mucosa remaining an unresolved problem. Through the delivery of the hydrogel with stent platform, we aimed to evaluate the regenerative capacity of a tissue-specific decellularized extracellular matrix (dECM) hydrogel on damaged tissues. For this, an esophagus-derived dECM (EdECM) was developed and shown to have superior biofunctionality and rheological properties, as well as physical stability, potentially providing a better microenvironment for tissue development. An EdECM hydrogel-loaded stent was sequentially fabricated using a rotating rod combined 3D printing system that showed structural stability and protected a loaded hydrogel during delivery. Finally, following stent implantation, the therapeutic effect of EdECM was examined in a radiation esophagitis rat model. Our findings demonstrate that EdECM hydrogel delivery via a stent platform can rapidly resolve an inflammatory response, thus promoting a pro-regenerative microenvironment. The results suggest a promising therapeutic strategy for the treatment of radiation esophagitis.

The feasibility and safety of radical esophagectomy in patients receiving neoadjuvant chemoradiotherapy with pembrolizumab for esophageal squamous cell carcinoma.

BACKGROUND: Immune checkpoint inhibitors have been tried for several thoracic malignancies; however, their application as a neoadjuvant therapy in esophageal squamous cell carcinoma (ESCC) has not been studied. We evaluated the feasibility and safety of esophagectomy and total lymphadenectomy after neoadjuvant chemoradiation therapy with pembrolizumab. METHODS: Between 2017 and 2018, 38 patients who received the neoadjuvant therapy followed by radical esophagectomy and total lymphadenectomy for ESCC were analyzed. Twenty-two patients received conventional neoadjuvant chemoradiation therapy (Group 1), and sixteen patients received neoadjuvant chemoradiation therapy with pembrolizumab in clinical trial (Group 2). Two groups were compared retrospectively. RESULTS: The basic characteristics of age, clinical stage, location and methods of operation were not different between the two groups. The pathologic stages were higher in Group 2, but the difference was not statistically significant. The operative outcomes, i.e., operation time, blood loss, and numbers of dissected lymph nodes in the thorax, neck, and abdomen were comparable. Complications, including pulmonary complications and anastomotic leakage, were also comparable. The rate of recurrent laryngeal nerve palsy was also comparable between the two groups (31.8% vs. 18.8%, P=0.469). Operative mortalities developed in 2 patients [0 vs. 2 (12.5%), P=0.171] due to acute respiratory distress syndrome (ARDS). CONCLUSIONS: Radical esophagectomy for esophageal squamous cell carcinoma after neoadjuvant chemoradiation therapy with pembrolizumab may not increase the operative risk or reduce the quality of radical dissection including lymphadenectomy. The risk of ARDS after neoadjuvant neoadjuvant chemoradiation therapy with pembrolizumab has to be studied in the further analysis.

Deletion Timing of Cic Alleles during Hematopoiesis Determines the Degree of Peripheral CD4+ T Cell Activation and Proliferation.

Capicua (CIC) is a transcriptional repressor that regulates several developmental processes. CIC deficiency results in lymphoproliferative autoimmunity accompanied by expansion of CD44hiCD62Llo effector/memory and follicular Th cell populations. Deletion of Cic alleles in hematopoietic stem cells (Vav1-Cre-mediated knockout of Cic) causes more severe autoimmunity than that caused by the knockout of Cic in CD4+CD8+ double positive thymocytes (Cd4-Cre-mediated knockout of Cic). In this study, we compared splenic CD4+ T cell activation and proliferation between whole immune cell-specific Cic-null (Cicf/f;Vav1-Cre) and T cell-specific Cic-null (Cicf/f;Cd4-Cre) mice. Hyperactivation and hyperproliferation of CD4+ T cells were more apparent in Cicf/f;Vav1-Cre mice than in Cicf/f;Cd4-Cre mice. Cicf/f;Vav1-Cre CD4+ T cells more rapidly proliferated and secreted larger amounts of IL-2 upon TCR stimulation than did Cicf/f;Cd4-Cre CD4+ T cells, while the TCR stimulation-induced activation of the TCR signaling cascade and calcium flux were comparable between them. Mixed wild-type and Cicf/f;Vav1-Cre bone marrow chimeras also exhibited more apparent hyperactivation and hyperproliferation of Cic-deficient CD4+ T cells than did mixed wild-type and Cicf/f;Cd4-Cre bone marrow chimeras. Taken together, our data demonstrate that CIC deficiency at the beginning of T cell development endows peripheral CD4+ T cells with enhanced T cell activation and proliferative capability.

Efficacy of DA-5204 (Stillen 2X) for patients with gastroesophageal reflux disease: A randomized, double-blind, placebo-controlled pilot study.

BACKGROUND/AIM: Proton pump inhibitor (PPI) alone is not satisfactory for the treatment of gastroesophageal reflux disease (GERD). Therefore, we investigated the efficacy of DA-5204 (Stillen 2X, 90 mg of Artemisia asiatica 95% ethanol extract per tablet) and PPI combination therapy on GERD in comparison to PPI alone. METHODS: This randomized, double-blind, placebo-controlled study randomly assigned 70 patients with endoscopically proven esophageal mucosal injury (Los Angeles classification grade A or B) into 2 groups: pantoprazole 40 mg once daily with DA-5204 twice daily (DA-5204 group) or pantoprazole 40 mg once daily with placebo twice daily (placebo group) for 4 weeks. The primary endpoint was endoscopic healing rate. The secondary endpoint was sufficient relief (≥50% reduction) of symptoms using GERD Questionnaire. RESULTS: Final analyses included 29 patients with the DA-5204 group and 30 patients with the placebo group. At weeks 4, there was no significant difference in the endoscopic healing rate between the 2 groups (DA-5204 vs placebo; 96.6% vs 93.3%; P = 1.000). However, the rate of residual minimal change was significantly lower in the DA-5204 group (5/28, 17.9%) than in the placebo group (17/28, 60.7%) (P < .001). The rates of symptom relief were not different between the DA-5204 group and the placebo group (all P > .05). CONCLUSION: Combined therapy with PPI and DA-5204 has no additional effect on the endoscopic healing rate compared to PPI alone. However, it may be beneficial in resolving minimal change.

Extent of resection and molecular pathologic subtype are potent prognostic factors of adult WHO grade II glioma.

We evaluated prognostic factors of adult low-grade glioma (LGG) according to the new 2016 WHO classification. Records of 153 patients diagnosed with WHO grade II LGG between 2003 and 2015 were retrospectively reviewed. Based on the 2016 WHO classification, 80 patients (52.3%) had diffuse astrocytoma, IDH-mutant; 45 (29.4%) had oligodendroglioma, IDH-mutant and 1p/19q-codeleted (ODG); and 28 (18.3%) had diffuse astrocytoma, IDH-wildtype. Gross total resection (GTR) was performed in 71 patients (46.4%), subtotal resection in 31 (20.3%), partial resection in 43 (28.1%), and biopsy in 8 (5.2%). One hundred two patients (66.7%) received postoperative radiotherapy. The 5- and 10-year progression-free survival (PFS) rates were 72.7% and 51.5%, respectively, and the 5- and 10-year overall survival (OS) rates were 82.5% and 63.5%, respectively. GTR and IDH-mutant and/or 1p/19q codeletion were favorable prognostic factors for PFS and OS. Patients with IDH-wildtype had significantly decreased OS. Among patients with ODG who underwent GTR, no recurrence was observed after radiotherapy. Patients who underwent non-GTR frequently experienced recurrence after radiotherapy (IDH-mutant: 47.6%, IDH-wildtype: 57.9%). In conclusion, molecular classification of LGG was of prognostic relevance, with IDH-wildtype patients having a particularly poor outcome, regardless of the treatment. Favorable results were observed in patients who underwent GTR.