Age and medial compartmental OA were important predictors of the lateral compartmental OA in the discoid lateral meniscus: Analysis using machine learning approach.

PURPOSE: The objective of this study was to develop a machine learning model that would predict lateral compartment osteoarthritis (OA) in the discoid lateral meniscus (DLM), from which to then identify factors contributing to lateral compartment OA, with a key focus on the patient's age. METHODS: Data were collected from 611 patients with symptomatic DLM diagnosed using magnetic resonance imaging between April 2003 and May 2022. Twenty features, including demographic, clinical and radiological data and six algorithms were used to develop the predictive machine learning models. Shapley additive explanation (SHAP) analysis was performed on the best model, in addition to subgroup analyses according to age. RESULTS: Extreme gradient boosting classifier was identified as the best prediction model, with an area under the receiver operating characteristic curve (AUROC) of 0.968, the highest among all the models, regardless of age (AUROC of 0.977 in young age and AUROC of 0.937 in old age). In the SHAP analysis, the most predictive feature was age, followed by the presence of medial compartment OA. In the subgroup analysis, the most predictive feature was age in young age, whereas the most predictive feature was the presence of medial compartment OA in old age. CONCLUSION: The machine learning model developed in this study showed a high predictive performance with regard to predicting lateral compartment OA of the DLM. Age was identified as the most important factor, followed by medial compartment OA. In subgroup analysis, medial compartmental OA was found to be the most important factor in the older age group, whereas age remained the most important factor in the younger age group. These findings provide insights that may prove useful for the establishment of strategies for the treatment of patients with symptomatic DLM. LEVEL OF EVIDENCE: Level III.

Factors associated with gastric and duodenal neuroendocrine tumors: A multicenter case-control study.

BACKGROUND AND AIMS: The incidence of gastric and duodenal neuroendocrine tumors (GNET and DNET, respectively) is increasing, however associated factors of these diseases are not well known. Here, we investigated the factors associated with GNET and DNET. METHODS: Patients with GNET and DNET presenting at eight tertiary referral centers between 2001 and 2020 were included and compared with healthy controls who underwent upper endoscopic screening. Clinical factors and laboratory data were analyzed to determine associated factors of GNET and DNET. RESULTS: Overall, 396 patients with GNET and 193 patients with DNET were included and compared with 1725 healthy controls. Multivariate analysis showed that age (odds ratio [OR] 0.98), diabetes (OR 1.72), hypertension (OR 1.97), low serum high-density lipoprotein cholesterol (HDL-C) levels (OR 2.54), and past/present H. pylori infection (OR 1.46) were significantly associated with GNET. In contrast, DNET was significantly associated with diabetes (OR 1.80), hypertension (OR 1.68), low serum HDL-C levels (OR 2.29), and past/present H. pylori infection (OR 5.42). In the sex-based subgroup analysis in GNET, current smoking was strongly associated in women (OR 9.85), but not in men. CONCLUSIONS: This study identified several common metabolic factors associated with GNET and DNET. Additionally, some factors had sex-specific associations.

Clinical impact of craniectomy on shunt-dependent hydrocephalus after intracerebral hemorrhage: A propensity score-matched analysis.

PURPOSE: A consensus on decompressive craniectomy for intracerebral hemorrhage (ICH) has not yet been established. We aimed to investigate the development of shunt-dependent hydrocephalus based on the method of ICH surgery, with a focus on craniectomy. METHODS: We retrospectively enrolled 458 patients with supratentorial ICH who underwent surgical hematoma evacuation between April 2005 and December 2021 at two independent stroke centers. Multivariate analyses were performed to characterize risk factors for postoperative shunt-dependent hydrocephalus. Propensity score matching (1:2) was undertaken to compensate for group-wise imbalances based on probable factors that were suspected to affect the development of hydrocephalus, and the clinical impact of craniectomy on shunt-dependent hydrocephalus was evaluated by the matched analysis. RESULTS: Overall, 43 of the 458 participants (9.4%) underwent shunt procedures as part of the management of hydrocephalus after ICH. Multivariate analysis revealed that intraventricular hemorrhage (IVH) and craniectomy were associated with shunt-dependent hydrocephalus after surgery for ICH. After propensity score matching, there were no statistically significant intergroup differences in participant age, sex, hypertension status, diabetes mellitus status, lesion location, ICH volume, IVH occurrence, or IVH severity. The craniectomy group had a significantly higher incidence of shunt-dependent hydrocephalus than the non-craniectomy group (28.9% vs. 4.3%, p < 0.001; OR 9.1, 95% CI 3.7-22.7), craniotomy group (23.2% vs. 4.3%, p < 0.001; OR 6.6, 95% CI 2.5-17.1), and catheterization group (20.0% vs. 4.0%, p = 0.012; OR 6.0, 95% CI 1.7-21.3). CONCLUSION: Decompressive craniectomy seems to increase shunt-dependent hydrocephalus among patients undergoing surgical ICH evacuation. The decision to perform a craniectomy for patients with ICH should be carefully individualized while considering the risk of hydrocephalus.

Postoperative Intravenous Iron Supplementation Increases Hemoglobin Level in Total Knee Arthroplasty.

Iron supplementation provides iron storage and facilitates effective production of hemoglobin. The purpose of this study was to investigate the effect of early postoperative intravenous (IV) iron supplementation in different types of total knee arthroplasty (TKA) surgery. We retrospectively analyzed 863 patients who underwent TKA between September 2017 and September 2021. The IV iron (I) and non-IV iron (NI) groups were compared. Hemoglobin responders, defined as patients who showed a change in hemoglobin level of ≥2 g/dL at 6 weeks of surgery compared to the baseline immediate postoperative hemoglobin level, were identified and they were compared with the nonresponders. After logistic regression analysis, the patients were classified according to the type of surgery (unilateral TKA, staged bilateral TKA, and simultaneous bilateral TKA). A subgroup analysis was performed according to the comorbidity as Charlson Comorbidity Index (CCI). The type of surgery and the rate of hemoglobin responders differed between the I and NI groups. The surgery type and iron supplementation significantly affected the hemoglobin responder in the logistic regression model. In each surgery type, hemoglobin drop in the I group was generally lower in the second and sixth weeks than that in the NI group. It was also effective in reducing hemoglobin drop on the first day of the second surgery in staged bilateral TKA. In addition, the number of hospital days was lower in the IV iron supplementation group who underwent a staged bilateral TKA. CCI did not affect hemoglobin responder, hemoglobin drop, and transfusion rate in both the I and NI groups. Postoperative IV iron supplementation affected the outcome of hemoglobin responders. In addition, it reduced early postoperative hemoglobin drop. However, iron supplementation did not affect the transfusion rate, complications, and clinical outcome, regardless of the type of surgery. LEVEL OF EVIDENCE: Level III, case-control study.

Retro-tubercular Biplanar Medial Opening-Wedge High Tibial Osteotomy Results in Superior Patellofemoral Alignment Versus Supra-tubercular Osteotomy.

PURPOSE: To compare the changes in patellofemoral (PF) joint alignment, focusing on multiple planes, between two different types of biplanar medial opening-wedge high tibial osteotomy (OWHTO). METHODS: Patients who underwent biplanar OWHTO between July 2017 and May 2021 were retrospectively evaluated. They were allocated to either the supra-tubercular (ST)- or retro-tubercular (RT)-OWHTO group. The following radiologic parameters were compared between the two groups: 1) weight-bearing line ratio (WBLR), 2) patellar height, 3) posterior tibial slope (PTS), 4) tibial tubercle-trochlear groove (TT-TG) distance, 5) TT-TG angle, and 6) femoral shaft-patellar tendon (FS-PT) angle. Clinical outcomes and the minimal clinically important difference (MCID) were also evaluated. RESULTS: In total, 104 knees that underwent ST-OWHTO and 105 knees that underwent RT-OWHTO were evaluated. The patellar height significantly decreased only after ST-OWHTO (P < .001). The TT-TG distance and FS-PT angle significantly increased, more after ST-OWHTO than RT-OWHTO (mean change value: 5.72 mm vs 1.91 mm; P < .001 for TT-TG distance; and 4.72° vs 1.80°; P < .001 for FS-PT angle). The TT-TG angle increased significantly after ST-OWHTO (mean change value: 7.62°; P < .001) but decreased after RT-OWHTO mean change value: -4.30°; P < .001). The PTS more increased after RT-OWHTO than after ST-OWHTO (mean change value: 0.91° vs 1.69°; P = .003). Clinical outcomes in both groups improved postoperatively, and no significant differences were observed between the groups. CONCLUSIONS: RT-OWHTO resulted in lesser changes in multiplane PF joint alignment than ST-OWHTO. However, no difference was observed in clinical outcomes between both groups, and PTS increased after RT-OWHTO. Therefore, these aspects of RT-OWHTO should also be considered. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Arthroscopic Meniscal Repair and Meniscectomy for Adult Discoid Lateral Meniscus Results in Progression to Valgus Alignment and Lateral Compartment Degeneration Compared With Nonoperative Treatment and Nondiscoid Lateral Meniscus.

PURPOSE: To analyze the effect of the arthroscopic meniscal procedure in adult discoid lateral meniscus (DLM) according to the age and meniscal-preserving by making comparisons with the nondiscoid lateral meniscus (N-DLM). METHODS: From March 2014 to October 2020, a comparative analysis was performed in adults with DLM who underwent arthroscopic meniscal procedures (operative DLM: 134 knees), nonoperative treatment (nonoperative DLM: 56 knees), and adult N-DLM who underwent arthroscopic meniscal procedures (operative N-DLM: 64 knees). These patients were between 20 and 65 years old and completed a minimum follow-up of 2 years. Patients with DLM who underwent arthroscopic procedure were divided into subgroups according to age and extent of the meniscal-preserving. The following parameters were assessed and compared between the groups: (1) coronal limb alignment, (2) osteoarthritis grade, and (3) clinical outcomes and the minimal clinically important difference. RESULTS: The coronal limb alignment was significantly changed to valgus in the order of operative DLM, N-DLM, and nonoperative DLM (Δ mechanical hip-knee-ankle angle: 3.23 ± 1.85 vs 1.35 ± 1.03° vs -0.57 ± 1.88°; P < .05). Operative DLM showed most prominent osteoarthritic change in the lateral compartment, followed by the N-DLM and nonoperative DLM groups (40.3% vs 17.2% vs 5.3%; P < .05). These changes in operative DLM were more prominent in older adults who underwent meniscal-sacrificing procedures and resulted in less-satisfactory clinical outcomes (all P < .05). CONCLUSIONS: Arthroscopic surgery for adult DLM resulted in progression to valgus alignment and lateral compartment degeneration compared with nonoperative treatment and arthroscopic surgery of the adult N-DLM. Old ager and having a meniscal-sacrificing procedure showed more rapid radiographic changes and lower clinical outcomes. LEVEL OF EVIDENCE: Level III, retrospective comparison study.

Constitutional alignment predicts medial ligament balancing in mechanically aligned total knee arthroplasty for varus knees.

PURPOSE: The aim of this study was to identify if constitutional alignment and preoperative radiologic parameters determined whether medial gap balancing was required in mechanically aligned total knee arthroplasty (TKA). METHODS: Two hundred and sixty three patients with 394 consecutive knees who underwent primary TKAs were retrospectively analysed in this study. Selective sequential multiple needle puncturing (MNP) was performed for medial ligament balancing when required. Constitutional alignment, which was determined using the Coronal Plane Alignment of the Knee (CPAK) classification, as well as preoperative and postoperative radiologic parameters was evaluated to identify factors which predicted the need for MNP. RESULTS: One hundred and fifty eight (40.1%) knees required medial ligament balancing with MNP. Patients who required MNP during surgery had significantly more constitutional varus, more varus preoperative mechanical Hip-Knee-Ankle angle (mHKA), smaller preoperative medial proximal tibial angle (MPTA) and a larger change in mHKA and MPTA after surgery than those who did not. Patients with constitutional varus also had a higher incidence of having had MNP to both anterior and posterior superficial medial collateral ligament (sMCL) fibres. There was no significant difference in preoperative lateral distal femoral angle (LDFA), posterior tibial slope (PTS) and varus-valgus difference (VVD) between groups. CONCLUSION: Ligament balancing using MNP was determined by constitutional alignment rather than medial soft tissue contracture. Patients with constitutional varus who had a larger medio-lateral gap difference in extension also had a higher incidence of having had MNP to both anterior and posterior sMCL fibres. LEVEL OF EVIDENCE: Retrospective comparative study, level IV.

Constitutional and postoperative joint line obliquity can predict serial alignment change after opening-wedge high tibial osteotomy: analysis using coronal plane alignment of the knee classification.

PURPOSE: The purposes of this study were (1) to clarify the distribution of the Coronal Plane Alignment of the Knee (CPAK) phenotype in patients who underwent medial opening-wedge high tibial osteotomy (OWHTO) and (2) to identify the predictive factors for postoperative serial alignment changes after OWHTO by analyzing constitutional phenotypes. METHODS: Patients who underwent OWHTO between March 2014 and December 2019 were retrospectively evaluated. Those who completed a minimum follow-up of 3 years were divided into three groups based on the direction of alignment changes from postoperative 3 months to the final follow-up: Group 1 (varus direction) when the weight-bearing line ratio (WBLR) change was less than - 4%, Group 2 (maintained) when the WBLR change was between - 4% and 4%, and Group 3 (valgus direction) when the WBLR change was greater than 4%. The following parameters were assessed serially and compared between the groups: (1) radiologic parameters of coronal limb alignment such as joint line obliquity (JLO), (2) CPAK phenotypes, and (3) clinical outcomes. RESULTS: In total, 163 knees were included, and the average duration of follow-up was 4.8 ± 1.6 years. More apex distal JLO was observed in the order of Group 1, 2, and 3 at all times (all p < 0.05). The most common CPAK type was type (I + II) (constitutional: apex distal JLO) + type (V + VI) (postoperative 3 months: neutral JLO) in Group 1 (29.4%; p = 0.000); otherwise, the most common CPAK type was type (IV + V) (constitutional: neutral JLO) + type (VIII + IX) (postoperative 3 months: apex proximal JLO) in Group 3 (11.7%; p = 0.000). Clinical outcomes did not differ between the groups. CONCLUSION: Constitutional and postoperative JLO were predictive factors of postoperative alignment changes after OWHTO. Constitutional apex distal and postoperative neutral JLO had a tendency for varus alignment progression, whereas constitutional neutral and postoperative apex proximal JLO had a tendency for valgus alignment progression. LEVEL OF EVIDENCE: Retrospective cohort study; Level III.

Graft impingement increases anterior cruciate ligament graft signal more than acute graft bending angle: magnetic resonance imaging-based study in outside-in anterior cruciate ligament reconstruction.

PURPOSE: In this study, the relationship between patient-specific geometric factors and tunnel placement in graft impingement was identified by using magnetic resonance imaging (MRI) signal intensity of anterior cruciate ligament (ACL) grafts. METHODS: Ninety-two patients, who were treated between 2014 and 2020, were included retrospectively. These patients underwent primary remnant-preserving outside-in ACL reconstruction (ACLR) and were followed up with postoperative MRI at least one year after surgery. Plain radiographs and computed tomography (CT) were used to analyze tibial and femoral tunnel positions. Postoperative MRI was performed, at 32.8 ± 17.5 months after surgery, to evaluate the graft signal intensity, the ACL/posterior cruciate ligament (PCL) ratio (APR), ACL/muscle ratio (AMR), tunnel positions, and graft impingement. Clinical and stability outcomes were analyzed using the International Knee Documentation Committee (IKDC) subjective and objective scores, Lysholm scores, and side-to-side differences (SS-D). RESULTS: The mean APR and AMR of the proximal third of the grafts were significantly lower than those of the middle third of the grafts (p = 0.017 and p = 0.045, respectively). Multivariate regression analysis showed that there was a negative association between the mean APR and AMR of entire intra-articular ACL graft and the distance from the anterior end of the intercondylar roof to the center of the tibial tunnel in the sagittal plane (p < 0.001 and p < 0.001, respectively) and the notch width index (p < 0.001 and p = 0.002, respectively). No significant correlations were found between tunneling and geometric factors, and clinical scores or SS-D. CONCLUSIONS: Graft impingement on the anterior tibial tunnel relative to the end of the intercondylar roof and narrow notch was a more significant contributing factor on increased signal intensities of the ACL graft, compared with the acute femoral bending angle in remnant-preserving outside-in ACLR. Therefore, surgeons should focus on intercondylar notch anatomy during tibial tunnel placement to avoid roof impingement. LEVEL OF EVIDENCE: Level III.

Serum pro-B-type natriuretic peptide levels and cardiac index as adjunctive tools of blunt cardiac injury.

BACKGROUND: Blunt cardiac injury (BCI) has a variety of symptoms that may be a potentially life-threatening injury that can lead to death. Depending on the diagnosis of BCI, treatment direction and length of stay may vary. In addition, the utility of other diagnostic tests for cardiac disease as diagnostic tools for BCI remain unclear. The purpose of this study was to investigate the competence of N-terminal pro-B-type natriuretic peptide (NT pro-BNP) and cardiac index (C.I) as adjunctive diagnostic tools for BCI. METHODS: From January 2018 to March 2020, severe trauma patients with sternum fracture who were admitted to the traumatic intensive care unit (TICU) were included this study. Patients with sternum fracture, 18 years of age or older, and with an injury severity score > 16 who required intensive care were included. Invasive measurement for the analysis of the pulse contour for C.I monitoring and intravenous blood sampling for NT pro-BNP measurement were performed. Sampling and 12-lead electrocardiogram were performed at different time points as follows: immediately after TICU admission and at 24 h and 48 h after trauma. RESULTS: Among 103; 33 patients with factors that could affect NT pro-BNP were excluded; therefore, 63 patients were included in this study. According to the American Association for the Surgery of Trauma Cardiac Injury Scale, 33 patients were diagnosed with non-BCI, and 30 patients constituted with BCI. The median ages of the patients were 58 (52-69), and 60 (45-69) years in the non-BCI and BCI groups, respectively (p = 0.77). The median NT pro-BNP values were higher in the BCI group on admission, hospital day (HD) 2, and HD 3, however, no statistical difference was observed (125 (49-245) vs. 130 (47-428) pg/mL, p = 0.08, 124 (68-224) vs. 187 (55-519) pg/mL, p = 0.09, and 121(59-225) vs. 133 (56-600) pg/mL, p = 0.17, respectively). On the contrary, significantly lower values were observed in the median C.I measurement on admission and HD 3 in the BCI group (3.2 (2.8-3.5) vs. 2.6 (2.3-3.5) L/min/m2, p < 0.01 and 3.2 (3.1-3.9) vs. 2.9 (2.4-3.2) L/min/m2, p < 0.01, respectively); however, no significant difference was observed on HD 2 (3.4 (3.0-3.7) vs. 2.6 (2.4-3.4) L/min/m2, p = 0.17), Furthermore, The median lactate levels in the BCI group upon admission, HD 2, and HD 3 were significantly higher than those in the non-BCI group (1.8 (1.1-2.6) vs. 3.1 (2.1-4.4) mmol/L, p < 0.01; 1.3 (0.8-2.3) vs. 3.0 (2.2-4.7) mmol/L, p < 0.01; and 1.5 (0.9-1.5) vs. 2.2 (1.3-3.7) mmol/L, p < 0.01, respectively). CONCLUSION: Consecutive values of NT pro-BNP and C.I show no correlation with ECG-based BCI diagnosis. However, lactate level measurement may help in the early recognition of BCI as an adjunctive tool. It should be noted that this is a hypothesis-generating study for BCI diagnosis. Further studies should be conducted in larger populations with a prospective approach.

Clinical Benefit of Bevacizumab and Irinotecan (BEV+IRI) in Patients With Relapsed/Refractory Glioblastoma (r/rGBM) and its Potential Predictors.

BACKGROUND/AIM: Bevacizumab-containing chemotherapy constitutes an important salvage treatment for recurrent/refractory glioblastoma(r/rGBM). PATIENTS AND METHODS: We retrospectively collected the data of r/rGBM patients treated with the combination of bevacizumab and irinotecan (BEV+IRI) as their salvage treatment from July 2013 and December 2021 in Konkuk Medical Center of Korea. Patients with available results from molecular diagnostic tests were eligible, and markers of interest were examined including the presence of MGMT methylation, IDH1/2 mutation, or 1p/19q co-deletion. Efficacy of BEV+IRI and its potential biomarker was explored. RESULTS: Among 21 patients, 38.1% demonstrated European Cooperative Oncology Group-Performance scale (ECOG-PS) ≥3. The majority (71.4%) received BEV+IRI as their second-line chemotherapies, and the median dose was 5 (range=1-25). Objective response rate (ORR) was 33.3% and disease-control rate (DCR) was 85.7%. Irrespective of objective response, early clinical response was achieved in 14(66.7%) patients. During the median follow-up of 16.4 months for survivors, median progression-free survival (PFS) and overall survival (OS) were 3.6 and 6.8 months, respectively. ECOG PS≥3 and TP53 loss were independent predictors of an unfavorable OS, while prompt clinical improvement could predict favorable OS. Any molecular aberration was associated with OS or PFS in the study. CONCLUSION: Salvage BEV+IRI treatment in r/rGBM conferred comparable clinical benefit. ECOG PS ≥3, TP53 loss, and lack of prompt clinical improvement after the treatment were significantly associated with an unfavorable OS.

Primary gastric dedifferentiated liposarcoma resected endoscopically: A case report.

BACKGROUND: Liposarcoma is one of the most common adult mesenchymal tumors but is uncommon in the gastrointestinal tract and extremely rare in the stomach. Furthermore, the histological subtypes of liposarcoma usually reported in the stomach are well-differentiated or myxoid, and few reports have been issued on small-sized gastric liposarcomas resected endoscopically and followed up. Herein, we report a case of primary gastric dedifferentiated liposarcoma (DL) that was resected endoscopically. CASE SUMMARY: A 67-year-old female Korean patient was referred to our institution for further evaluation of a gastric submucosal tumor (SMT) located in the lesser curvature of the gastric body by esophagogastroduodenoscopy. Endoscopic ultrasound revealed a well-circumscribed, slightly heterogeneous, isoechoic, 17 mm × 10 mm sized mass originating from the third sonographic layer. Computed tomography showed no evidence of significant lymph node enlargement or distant metastasis. Endoscopic resection was undertaken using the snare resection technique after mucosal precutting to provide a definitive histopathologic diagnosis, which proved to be consistent with DL, based on its morphology and the immunoexpressions of MDM2 and CDK4. The patient was planned for surgery because the deep resection margin was positive for malignancy. After declining any invasive procedure or adjuvant treatment, the patient was placed under close follow-up, and at one year after endoscopic resection, remained disease free. CONCLUSION: This is the first reported case of a small primary gastric DL resected endoscopically and followed up. This report demonstrates that when diagnosis of a SMT is uncertain, the use of invasive techniques, including endoscopic resection, should be considered.

Early gastric cancer presenting as a typical submucosal tumor cured by endoscopic submucosal dissection: A case report.

BACKGROUND: Submucosal tumor (SMT)-like gastric cancer is rare, and almost all cases undergo curative surgical treatment because the submucosal layer is usually deeply invaded by tumor cells or because histopathologic types of SMT-like gastric cancer are undifferentiated or poorly differentiated. No report has been issued on an SMT-like gastric cancer cured by endoscopic resection alone or on changes in the endoscopic features of this type of tumor over several years. CASE SUMMARY: We describe an exceptional case of a 53-year-old male with a 1.5 cm-sized SMT-like lesion covered by normal-appearing mucosa discovered by esophagogastroduodenoscopy (EGD) at the gastric antrum. Endoscopic ultrasound (EUS) visualized a homogeneous, well-circumscribed hypoechogenic lesion arising from the second sonographic layer with associated subtle obliteration of the third sonographic layer. Initial endoscopic biopsy was negative for neoplasm. The patient refused to undergo an invasive procedure and was subsequently lost to follow-up. Three years after initial detection, EGD revealed the lesion had become markedly erythematous, and at 4 years after initial EGD it had increased in size to 1.8 cm and developed a central ulcer and a heterogeneous EUS echo. Finally, endoscopic submucosal dissection (ESD) was performed, and histopathologic examination revealed a moderately differentiated adenocarcinoma had minutely invaded the submucosal layer (invasion depth 169 µm) but without lymphovascular invasion and with negative resection margins. Fortunately, no additional surgical treatment was required. He has been followed for 4 years after ESD without any evidence of local or distant recurrence. CONCLUSION: This report describes an extremely rare case of early gastric cancer presenting as SMT that was cured by ESD after a treatment delay of 4 years and the endoscopic changes that occurred during this period. The report highlights the importance of considering the possibility of gastric cancer when SMT is encountered in clinical practice.

Phosphodiesterase 5 inhibitor mirodenafil ameliorates Alzheimer-like pathology and symptoms by multimodal actions.

BACKGROUND: Alzheimer's disease (AD) pathology is associated with complex interactions among multiple factors, involving an intertwined network of various signaling pathways. The polypharmacological approach is an emerging therapeutic strategy that has been proposed to overcome the multifactorial nature of AD by targeting multiple pathophysiological factors including amyloid-ß (Aß) and phosphorylated tau. We evaluated a blood-brain barrier penetrating phosphodiesterase 5 (PDE5) inhibitor, mirodenafil (5-ethyl-2-7-n-propyl-3,5-dihydrro-4H-pyrrolo[3,2-d]pyrimidin-4-one), for its therapeutic effects on AD with polypharmacological properties. METHODS: To evaluate the potential of mirodenafil as a disease-modifying AD agent, mirodenafil was administered to test its effects on the cognitive behaviors of the APP-C105 AD mouse model using the Morris water maze and passive avoidance tests. To investigate the mechanisms of action that underlie the beneficial disease-modifying effects of mirodenafil, human neuroblastoma SH-SY5Y cells and mouse hippocampal HT-22 cells were used to show mirodenafil-induced alterations associated with the cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG)/cAMP-responsive element-binding protein (CREB) pathway, apoptotic cell death, tau phosphorylation, amyloidogenesis, the autophagy-lysosome pathway, glucocorticoid receptor (GR) transcriptional activity, and the Wnt/ß-catenin signaling. RESULTS: Here, mirodenafil is demonstrated to improve cognitive behavior in the APP-C105 mouse model. Mirodenafil not only reduced the Aß and phosphorylated tau burdens in vivo, but also ameliorated AD pathology induced by Aß through the modulation of the cGMP/PKG/CREB signaling pathway, glycogen synthase kinase 3ß (GSK-3ß) activity, GR transcriptional activity, and the Wnt/ß-catenin signaling in neuronal cells. Interestingly, homodimerization and nuclear localization of GR were inhibited by mirodenafil, but not by other PDE5 inhibitors. In addition, only mirodenafil reduced the expression levels of the Wnt antagonist Dickkopf-1 (Dkk-1), thus activating the Wnt/ß-catenin signaling. CONCLUSIONS: These findings strongly suggest that the PDE5 inhibitor mirodenafil shows promise as a potential polypharmacological drug candidate for AD treatment, acting on multiple key signaling pathways involved in amyloid deposition, phosphorylated tau burden, the cGMP/PKG/CREB pathway, GSK-3ß kinase activity, GR signaling, and the Wnt/ß-catenin signaling. Mirodenafil administration to the APP-C105 AD mouse model also improved cognitive behavior, demonstrating the potential of mirodenafil as a polypharmacological AD therapeutic agent.

Clinical outcomes of endoscopic resection of superficial nonampullary duodenal epithelial tumors: A 10-year retrospective, single-center study.

BACKGROUND: Although premalignant duodenal lesions such as adenomas are uncommon, the incidences of these lesions have increased in recent times, and thus, the demand for minimally invasive treatments such as endoscopic resection (ER) has also increased. However, ER in the duodenum is more challenging than ER in other locations of the gastrointestinal tract. AIM: To evaluate the safety and efficacy of ER for superficial nonampullary duodenal epithelial tumors (SNADETs). METHODS: We performed a retrospective observational study on 56 consecutive patients (58 lesions) diagnosed with SNADETs that underwent ER from January 2011 to December 2020 at Yeungnam University Hospital. Patient demographics, lesion characteristics, and procedural and technical data were collected, and clinical outcomes, including procedure-related complications, completeness of resection, and recurrence were analyzed. RESULTS: Median patient age was 57 years [range, 26-77, 30 (53.6%) men]. Endoscopic mucosal resection (EMR) was performed on 57 lesions (98.3%) and snare polypectomy on one (1.7%). Lesions consisted of 52 adenomas with low-grade dysplasia (89.7%), 3 adenomas with high-grade dysplasia (5.2%), and 3 intramucosal adenocarcinomas (5.2%). There were 16 cases of intraprocedural bleeding (27.6%) and 1 case of delayed bleeding (1.7%), and all these 17 cases were successfully managed endoscopically. No perforation or procedure-related death occurred. Larger lesion size was associated with an increased risk of EMR-related bleeding (P = 0.033). During a median follow-up period of 23 mo (range 6-100 mo), no local recurrence occurred, despite the fact one-third of the patients (19 lesions, 32.8%) underwent piecemeal resection and 3 patients (3 lesions, 5.2%) that underwent en bloc resection had a pathologically determined positive lateral margin. No patient died from a primary duodenal neoplasm. CONCLUSION: The majority of SNADETs can be safely and curatively resected by EMR, and thus, based on consideration of the high incidence of fatal complications attributable to ESD, we conclude EMR, including piecemeal resection, should be considered the treatment of first choice for SNADETs.

Prediction of Shunt-Dependent Hydrocephalus after Primary Supratentorial Intracerebral Hemorrhage with a Focus on the Influence of Craniectomies.

OBJECTIVE: Hydrocephalus after intracerebral hemorrhage (ICH) is known to be related to poor prognosis and mortality. We analyzed predictors of permanent hydrocephalus in the patients with surgically treated supratentorial ICH. METHODS: From 2004 to 2019, a total of 414 patients with surgically treated primary supratentorial ICH were included. We retrospectively analyzed age, sex, preexisting hypertension and diabetes, location and volume of ICH, presence and severity of intraventricular hemorrhage (IVH), and type of surgery. RESULTS: Forty patients (9.7%) required shunt surgery. Concomitant IVH was higher in the 'shunt required' group (92.5%) than in the 'shunt not required' group (67.9%) (p=0.001). IVH severity was worse in the 'shunt required' group (13.5 vs. 7.5, p=0.008). Craniectomy (47.5%) was significantly high in the 'shunt required' group. According to multivariable analysis, the presence of an IVH was 8.1 times more frequent and craniectomy was 8.6 times more frequent in the 'shunt required' group. In the comparison between craniotomy and craniectomy group, the presence of an IVH was related with a 3.9 times higher (p=0.033) possibility and craniectomies rather than craniotomies with a 7-times higher possibility of shunt surgery (p<0.001). Within the craniectomy group, an increase in the craniectomy area by 1 cm2 was correlated with a 3.2% increase in the possibility of shunt surgery (odds ratio, 1.032; 95% confidence interval, 1.005-1.061; p=0.022). CONCLUSION: Presence of IVH, the severity of IVH and decompressive craniectomy were related to the development of shunt dependent hydrocephalus in the patients with ICH. The increasing size of craniectomy was related with increasing rate of shunt requirement.

Comparison of cisplatin-induced anti-tumor response in CT26 syngeneic tumors of three BALB/c substrains.

BACKGROUND: To determine whether the background of BALB/c substrains affects the response to anti-tumor drugs, we measured for alterations in tumor growth, histopathological structure of the tumor, and expressions of tumor-related proteins in three BALB/c substrains derived from different sources (BALB/cKorl, BALB/cA and BALB/cB), after exposure to varying concentrations of cisplatin (0.1, 1 and 5 mg/kg). RESULTS: Cisplatin treatment induced similar responses for body and organ weights, serum analyzing factors, and blood analyzing factors in all BALB/c substrains with CT26 syngeneic tumor. Few differences were detected in the volume and histopathological structure of the CT26 tumor. Growth inhibition of CT26 tumors after exposure to cisplatin was greater in the BALB/cB substrain than BALB/cKorl and BALB/cA substrains, and a similar pattern was observed in the histopathological structure of tumors. However, the expression levels of other tumor-related factors, including Ki67, p27, p53, Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), caspase-3 (Cas-3), matrix metallopeptidase 2 (MMP2) and vascular endothelial growth factor (VEGF) proteins, were constantly maintained in the tumors of all three substrains after cisplatin treatment. A similar decrease pattern was observed for the expressions of inflammatory cytokines, including interleukin (IL)-1ß, IL-6 and IL-10, in the CT26 tumors of the three BALB/c substrains. CONCLUSIONS: Taken together, results of the present study indicate that the genetic background of the three BALB/c substrains has no major effect on the therapeutic responsiveness of cisplatin, except growth and histopathology of the CT26 syngeneic tumor.

Comparison of intrinsic exercise capacity and response to acute exercise in ICR (Institute of Cancer Research) mice derived from three different lineages.

BACKGROUND: As a laboratory animal resource, the ICR mouse is commonly used in a variety of research fields. However, information on differences in exercise-related characteristics in ICR mice derived from different lineages and the underlying mechanisms remains to be elucidated. In this study, we investigated the intrinsic exercise capacity and a magnitude of response to acute exercise, and sought to identify mechanisms contributing to difference in Korl:ICR (a novel ICR lineage recently established by the National Institute of Food and Drug Safety Evaluation, Korea) and two commercialized ICR lineages derived from different origins (viz., A:ICR mouse from Orient Bio Com, the United States, and B:ICR mouse from Japan SLC Inc., Japan). RESULTS: Results showed that despite no significant difference in body weight and weight-proportioned tissue mass of heart and skeletal muscles among groups, the relatively low intrinsic exercise capacity and exaggerated response to acute exercise were identified in B:ICR comparted with Korl:ICR and A:ICR, as reflected by total work and lactate threshold (LT). Also, the mitochondrial efficiency expressed as the complex 1 and complex 1 + 2 respiratory control ratio (RCR) values for cardiac mitochondrial O2 consumption in B:ICR was significantly lower than that in Korl:ICR with higher level of state 2 respiration by glutamate/malate and UCP3 expression in cardiac muscle. CONCLUSIONS: Taken together, these results indicate that the intrinsic exercise capacity of ICR mouse varies according to lineages, suggesting the role of cardiac mitochondrial coupling efficiency as a possible mechanism that might contribute to differences in the intrinsic exercise capacity and magnitude of response to exercise.