Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer.

BACKGROUND: No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma. METHODS: We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival. RESULTS: A total of 886 patients underwent randomization: 442 to the enfortumab vedotin-pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group. CONCLUSIONS: Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.).

ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma.

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600 mutant cells1-3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.

Nuclear Localization of Yes-Associated Protein Is Associated With Tumor Progression in Cutaneous Melanoma.

Yes-associated protein (YAP), an effector molecule of the Hippo signaling pathway, is expressed at high levels in cutaneous melanoma. However, the role of YAP in melanoma progression according to cellular localization is poorly understood. Tissues from 140 patients with invasive melanoma were evaluated by immunohistochemistry. Flow cytometry, western blotting, viability assays, wound healing assays, verteporfin treatment, and xenograft assays were conducted using melanoma cell lines B16F1 and B16F10 subjected to YapS127A transfection and siYap knockdown. Nuclear YAP localization was identified in 63 tumors (45.0%) and was more frequent than cytoplasmic YAP in acral lentiginous and nodular subtypes (P = .007). Compared with cytoplasmic YAP melanomas, melanomas with nuclear YAP had higher mitotic activity (P = .016), deeper invasion (P < .001), and more frequently metastasized to lymph nodes (P < .001) and distant organs (P < .001). Patients with nuclear YAP melanomas had poorer disease-free survival (P < .001) and overall survival (P < .001). Nuclear YAP was an independent risk factor for distant metastasis (hazard ratio: 3.206; 95% CI, 1.032-9.961; P = .044). Proliferative ability was decreased in siYapB16F1 (P < .001) and siYapB16F10 (P = .001) cells and increased in YapS127AB16F1 (P = .003) and YapS127AB16F10 (P = .002) cells. Cell cycle analysis demonstrated relative G1 retention in siYapB16F1 (P < .001) and siYapB16F10 (P < .001) cells and S retention in YapS127AB16F1 cells (P = .008). Wound healing assays showed that Yap knockdown inhibited cell invasion (siYapB16F1, P = .001; siYapB16F10, P < .001), whereas nuclear YAP promoted it (YapS127AB16F, P < .001; YapS127AB16F1, P = .017). Verteporfin, a direct YAP inhibitor, reduced cellular proliferation in B16F1 (P = .003) and B16F10 (P < .001) cells. Proliferative effects of nuclear YAP were confirmed in xenograft mice (P < .001). In conclusion, nuclear YAP in human melanomas showed subtype specificity and correlated with proliferative activity and proinvasiveness. It is expected that YAP becomes a useful prognostic marker, and its inhibition may be a potential therapy for melanoma patients.

The Lancet Commission to reduce the global burden of sudden cardiac death: a call for multidisciplinary action.

Despite major advancements in cardiovascular medicine, sudden cardiac death (SCD) continues to be an enormous medical and societal challenge, claiming millions of lives every year. Efforts to prevent SCD are hampered by imperfect risk prediction and inadequate solutions to specifically address arrhythmogenesis. Although resuscitation strategies have witnessed substantial evolution, there is a need to strengthen the organisation of community interventions and emergency medical systems across varied locations and health-care structures. With all the technological and medical advances of the 21st century, the fact that survival from sudden cardiac arrest (SCA) remains lower than 10% in most parts of the world is unacceptable. Recognising this urgent need, the Lancet Commission on SCD was constituted, bringing together 30 international experts in varied disciplines. Consistent progress in tackling SCD will require a completely revamped approach to SCD prevention, with wide-sweeping policy changes that will empower the development of both governmental and community-based programmes to maximise survival from SCA, and to comprehensively attend to survivors and decedents' families after the event. International collaborative efforts that maximally leverage and connect the expertise of various research organisations will need to be prioritised to properly address identified gaps. The Commission places substantial emphasis on the need to develop a multidisciplinary strategy that encompasses all aspects of SCD prevention and treatment. The Commission provides a critical assessment of the current scientific efforts in the field, and puts forth key recommendations to challenge, activate, and intensify efforts by both the scientific and global community with new directions, research, and innovation to reduce the burden of SCD worldwide.

Exploring Molecular Genetic Alterations and RAF Fusions in Melanoma: A Belvarafenib Expanded Access Program in Patients with RAS/RAF-Mutant Melanoma.

BACKGROUND: Melanoma incidence is on the rise in East Asia, yet studies of the molecular landscape are lacking in this population. We examined patients with melanoma who underwent next-generation sequencing (NGS) at a single tertiary center in South Korea, focusing on patients harboring NRAS or RAF alterations who received belvarafenib, a pan-RAF dimer inhibitor, through the Expanded Access Program (EAP). PATIENTS AND METHODS: Data were collected from 192 patients with melanoma who underwent NGS between November 2017 and May 2023. Variant call format data were obtained and annotated. Patients in the EAP received 450 mg twice daily doses of belvarafenib. RESULTS: Alterations in the RAS/RTK pathway were the most prevalent, with BRAF and NRAS alteration rates of 22.4% and 17.7%, respectively. NGS enabled additional detection of fusion mutations, including 6 BRAF and 1 RAF1 fusion. Sixteen patients with NRAS or RAF alterations received belvarafenib through the EAP, and disease control was observed in 50%, with 2 patients demonstrating remarkable responses. CONCLUSIONS: Our study highlights the value of NGS in detecting BRAF, NRAS mutations and RAF fusions, expanding possibilities for targeted therapies in malignant melanoma. Belvarafenib showed clinical benefit in patients harboring these alterations. Ongoing trials will provide further insights into the safety and efficacy of belvarafenib.

Analysis of the global transcriptome and miRNAome associated with seed dormancy during seed maturation in rice (Oryza sativa L. cv. Nipponbare).

BACKGROUND: Seed dormancy is a biological mechanism that prevents germination until favorable conditions for the subsequent generation of plants are encountered. Therefore, this mechanism must be effectively established during seed maturation. Studies investigating the transcriptome and miRNAome of rice embryos and endosperms at various maturation stages to evaluate seed dormancy are limited. This study aimed to compare the transcriptome and miRNAome of rice seeds during seed maturation. RESULTS: Oryza sativa L. cv. Nipponbare seeds were sampled for embryos and endosperms at three maturation stages: 30, 45, and 60 days after heading (DAH). The pre-harvest sprouting (PHS) assay was conducted to assess the level of dormancy in the seeds at each maturation stage. At 60 DAH, the PHS rate was significantly increased compared to those at 30 and 45 DAH, indicating that the dormancy is broken during the later maturation stage (45 DAH to 60 DAH). However, the largest number of differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs) were identified between 30 and 60 DAH in the embryo and endosperm, implying that the gradual changes in genes and miRNAs from 30 to 60 DAH may play a significant role in breaking seed dormancy. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses confirmed that DEGs related to plant hormones were most abundant in the embryo during 45 DAH to 60 DAH and 30 DAH to 60 DAH transitions. Alternatively, most of the DEGs in the endosperm were related to energy and abiotic stress. MapMan analysis and quantitative real-time polymerase chain reaction identified four newly profiled auxin-related genes (OsSAUR6/12/23/25) and one ethylene-related gene (OsERF087), which may be involved in seed dormancy during maturation. Additionally, miRNA target prediction (psRNATarget) and degradome dataset (TarDB) indicated a potential association between osa-miR531b and ethylene biosynthesis gene (OsACO4), along with osa-miR390-5p and the abscisic acid (ABA) exporter-related gene (OsMATE19) as factors involved in seed dormancy. CONCLUSIONS: Analysis of the transcriptome and miRNAome of rice embryos and endosperms during seed maturation provided new insights into seed dormancy, particularly its relationship with plant hormones such as ABA, auxin, and ethylene.

Characteristic of school injuries in Asia: a cross-national, multi-center observational study.

BACKGROUND: To prevent school injuries, thorough epidemiological data is an essential foundation. We aimed to investigate the characteristics of school injuries in Asia and explore risk factors for major trauma. METHODS: This retrospective study was conducted in the participating centers of the Pan-Asian Trauma Outcome Study from October 2015 to December 2020. Subjects who reported "school" as the site of injury were included. Major trauma was defined as an Injury Severity Score (ISS) value of ≥16. RESULTS: In total, 1305 injury cases (1.0% of 127,715 events) occurred at schools. Among these, 68.2% were children. Unintentional injuries were the leading cause and intentional injuries comprised 7.5% of the cohort. Major trauma accounted for 7.1% of those with documented ISS values. Multivariable regression revealed associations between major trauma and factors, including age, intention of injury (self-harm), type of injury (traffic injuries, falls), and body part injured (head, thorax, and abdomen). Twenty-two (1.7%) died, with six deaths related to self-harm. Females represented 28.4% of injuries but accounted for 40.9% of all deaths. CONCLUSIONS: In Asia, injuries at schools affect a significant number of children. Although the incidence of injuries was higher in males, self-inflicted injuries and mortality cases were relatively higher in females. IMPACT: Epidemiological data and risk factors for major trauma resulting from school injuries in Asia are lacking. This study identified significant risk factors for major trauma occurring at schools, including age, intention of injury (self-harm), injury type (traffic injuries, falls), and body part injured (head, thoracic, and abdominal injuries). Although the incidence of injuries was higher in males, the incidence of self-harm injuries and mortality rates were higher in females. The results of this would make a significant contribution to the development of prevention strategies and relative policies concerning school injuries.

Structural optimization and biological evaluation of ML364 based derivatives as USP2a inhibitors.

Ubiquitination is a representative post-translational modification that tags target proteins with ubiquitin to induce protein degradation or modify their functions. Deubiquitinating enzymes (DUBs) play a crucial role in reversing this process by removing ubiquitin from target proteins. Among them, USP2a has emerged as a promising target for cancer therapy due to its oncogenic properties in various cancer types, but its inhibitors have been limited. In this study, our aim was to optimize the structure of ML364, a USP2a inhibitor, and synthesize a series of its derivatives to develop potent USP2a inhibitors. Compound 8v emerged as a potential USP2a inhibitor with lower cytotoxicity compared to ML364. Cellular assays demonstrated that compound 8v effectively reduced the levels of USP2a substrates and attenuated cancer cell growth. We confirmed its direct interaction with the catalytic domain of USP2a and its selective inhibitory activity against USP2a over other USP subfamily proteins (USP7, 8, or 15). In conclusion, compound 8v has been identified as a potent USP2a inhibitor with substantial potential for cancer therapy.

Vitamin D deficiency as a risk factor for sudden cardiac arrest: A multicenter case-control study.

BACKGROUND AND AIMS: Vitamin D is known to influence the risk of cardiovascular disease, which is a recognized risk factor for sudden cardiac arrest (SCA). However, the relationship between vitamin D and SCA is not well understood. Therefore, this study aims to investigate the association between vitamin D and SCA in out-of-hospital cardiac arrest (OHCA) patients compared to healthy controls. METHODS AND RESULTS: Using the Phase II Cardiac Arrest Pursuit Trial with Unique Registration and Epidemiologic Surveillance (CAPTURES II) registry, a 1:1 propensity score-matched case-control study was conducted between 2017 and 2020. Serum 25-hydroxyvitamin D (vitamin D) levels in patients with OHCA (454 cases) and healthy controls (454 cases) were compared after matching for age, sex, cardiovascular risk factors, and lifestyle behaviors. The mean vitamin D levels were 14.5 ± 7.6 and 21.3 ± 8.3 ng/mL among SCA cases and controls, respectively. Logistic regression analysis was used adjusting for cardiovascular risk factors, lifestyle behaviors, corrected serum calcium levels, and estimated glomerular filtration rate (eGRF). The adjusted odds ratio (aOR) for vitamin D was 0.89 (95% confidence interval [CI] 0.87-0.91). The dose-response relationship demonstrated that vitamin D deficiency was associated with SCA incidence (severe deficiency, aOR 10.87, 95% CI 4.82-24.54; moderate deficiency, aOR 2.24, 95% CI 1.20-4.20). CONCLUSION: Vitamin D deficiency was independently and strongly associated with an increased risk of SCA, irrespective of cardiovascular and lifestyle factors, corrected calcium levels, and eGFR.

USP35 dimer prevents its degradation by E3 ligase CHIP through auto-deubiquitinating activity.

Recently, a number of reports on the importance of USP35 in cancer have been published. However, very little is known about the exact mechanism by which USP35 activity is regulated. Here, we show the possible regulation of USP35 activity and the structural specificity affecting its function by analyzing various fragments of USP35. Interestingly, the catalytic domain of USP35 alone does not exhibit deubiquitinating activity; in contrast, the C-terminal domain and insertion region in the catalytic domain is required for full USP35 activity. Additionally, through its C-terminal domain, USP35 forms a homodimer that prevents USP35 degradation. CHIP bound to HSP90 interacts with and ubiquitinates USP35. However, when fully functional USP35 undergoes auto-deubiquitination, which attenuates CHIP-mediated ubiquitination. Finally, USP35 dimer is required for deubiquitination of the substrate Aurora B and regulation of faithful mitotic progression. The properties of USP35 identified in this study are a unique homodimer structure, regulation of deubiquitinating activity through this, and utilization of a novel E3 ligase involved in USP35 auto-deubiquitination, which adds another complexity to the regulation of deubiquitinating enzymes.

Association Between Ambulance Station Case Volume and Clinical Outcomes in Moderate to Severe Trauma.

OBJECTIVES: The effect of the case volume of emergency medical services (EMS) on the clinical outcomes of trauma is uncertain. The purpose of this study was to evaluate the association between the case volume of an ambulance station and clinical outcomes in moderate to severe trauma patients. METHODS: Adult trauma patients with injury severity scores greater than 8 who were transported by the EMS between 2018 and 2019 were analyzed. The main exposure was the annual case volume of moderate to severe trauma at the ambulance station where the patient-transporting ambulance was based: low-volume (less than 60 cases), intermediate-volume (between 60 and 89 cases), and high-volume (equal or greater than 90 cases). The primary outcome was in-hospital mortality. Multilevel multivariable logistic regression analysis was conducted to calculate adjusted odds ratios (AORs) and 95% confidence intervals (CIs), with the high-volume group used as the reference. RESULTS: In total, 21,498 trauma patients were analyzed. The high-volume group exhibited lower in-hospital mortality, 447 (9.0%), compared to 867 (14.1%) in the intermediate-volume group and 1,458 (14.1%) in the low-volume group. There were a significantly higher odds of in-hospital mortality: the low-volume group (AOR 95% CI: 1.20 (0.95-1.51)) and intermediate-volume group (AOR 95% CI: 1.29 (1.02-1.64)) when compared to the high-volume group. CONCLUSIONS: The case volume at an ambulance station is associated with in-hospital mortality in patients with moderate to severe trauma. These results should be considered when constructing an EMS system and education program for prehospital trauma care.

Association between Case Volumes of Extracorporeal Life Support and Clinical Outcome in Out-of-Hospital Cardiac Arrest.

AIM: Extracorporeal life support (ECLS) for out-of-hospital cardiac arrest (OHCA) is increasing. There is little evidence identifying the association between hospital ECLS case volumes and outcomes in different populations receiving ECLS or conventional cardiopulmonary resuscitation (CPR). The goal of this investigation was to identify the association between ECLS case volumes and clinical outcomes of OHCA patients. METHODS: This cross-sectional observational study used the National OHCA Registry for adult OHCA cases in Seoul, Korea between January 2015 and December 2019. If the ECLS volume during the study period was >20, the institution was defined as a high-volume ECLS center. Others were defined as low-volume ECLS centers. Outcomes were good neurologic recovery (cerebral performance category 1 or 2) and survival to discharge. We performed multivariate logistic regression and interaction analyses to assess the association between case volume and clinical outcome. RESULTS: Of the 17,248 OHCA cases, 3,731 were transported to high-volume centers. Among the patients who underwent ECLS, those at high-volume centers had a higher neurologic recovery rate than those at low-volume centers (17.0% vs. 12.0%), and the adjusted OR for good neurologic recovery was 2.22 (95% confidence interval (CI): 1.15-4.28) in high-volume centers compared to low-volume centers. For patients who received conventional CPR, high-volume centers also showed higher survival-to-discharge rates (adjusted OR of 1.16, 95%CI: 1.01-1.34). CONCLUSIONS: High-volume ECLS centers showed better neurological recovery in patients who underwent ECLS. High-volume centers also had better survival-to-discharge rates than low-volume centers for patients not receiving ECLS.

Modified physiologic criteria for the field triage scheme: Efficacy of major trauma recognition in different age groups in Asia.

BACKGROUND: Major trauma is a leading cause of unexpected death globally, with increasing age-adjusted death rates for unintentional injuries. Field triage schemes (FTSs) assist emergency medical technicians in identifying appropriate medical care facilities for patients. While full FTSs may improve sensitivity, step-by-step field triage is time-consuming. A simplified FTS (sFTS) that uses only physiological and anatomical criteria may offer a more rapid decision-making process. However, evidence for this approach is limited, and its performance in identifying all age groups requiring trauma center resources in Asia remains unclear. METHODS: We conducted a multinational retrospective cohort study involving adult trauma patients admitted to emergency departments in the included countries from 2016 to 2020. Prehospital and hospital data were reviewed from the Pan-Asia Trauma Outcomes Study database. Patients aged ≥18 years transported by emergency medical services were included. Patients lacking data regarding age, sex, physiological criteria, or injury severity scores were excluded. We examined the performance of sFTS in all age groups and fine-tuned physiological criteria to improve sFTS performance in identifying high-risk trauma patients in different age groups. RESULTS: The sensitivity and specificity of the physiological and anatomical criteria for identifying major trauma (injury severity score ≥ 16) were 80.6% and 58.8%, respectively. The modified sFTS showed increased sensitivity and decreased specificity, with more pronounced changes in the young age group. Adding the shock index further increased sensitivity in both age groups. CONCLUSIONS: sFTS using only physiological and anatomical criteria is suboptimal for Asian adult patients with trauma of all age groups. Adjusting the physiological criteria and adding a shock index as a triage tool can improve the sensitivity of severely injured patients, particularly in young age groups. A swift field triage process can maintain acceptable sensitivity and specificity in severely injured patients.

The efficacy of slow-rate ventriculolumbar perfusion chemotherapy for leptomeningeal carcinomatosis: a phase II study.

PURPOSE: This study aimed to evaluate the symptomatic response and side effects of ventriculolumbar perfusion (VLP) methotrexate chemotherapy with a low perfusion rate in patients with leptomeningeal metastasis. METHODS: Patients in a single-arm, two-stage phase II trial based on Simon's minimax design received VLP with a reduced (15 cc/h) perfusion rate with the purpose of decreasing constitutional side effects such as nausea/vomiting, insomnia, and confusion. The primary outcome was control of increased intracranial pressure (ICP). The secondary outcome was an occurrence of side effects. The results were compared with those of a previous trial of VLP with a 20-cc/h perfusion rate. RESULTS: Total 90 patients were enrolled. Out of 65 patients with increased ICP, 32 achieved normalized ICP after VLP chemotherapy (bias-adjusted response rate = 51%). The incidence of moderate-to-severe nausea/vomiting was reduced to 46% from 64% in the previous study, and that of sleep disturbance was increased to 13% from 9%, but both failed to reach statistical significance. The incidence of moderate-to-severe confusion was significantly reduced to 12% from 23% in the previous study (p = 0.04). Median overall survival was better among patients with controlled ICP than among those who remained with increased ICP (193 days vs. 94 days, p = 0.013). CONCLUSION: Compared with a higher perfusion rate, the low perfusion rate failed to provide non-inferior ICP control or improved side effects, except for confusion. The relationship between VLP perfusion rate and ICP control needs to be evaluated in future trials adjusting for bias from uncompleted protocol due to poor general condition.

Postoperative Graft Volume Reduction Is Associated With Inferior Clinical Outcomes of Superior Capsule Reconstruction Using an Acellular Dermal Matrix Allograft.

PURPOSE: To evaluate whether postoperative graft volume reduction is associated with clinical outcomes after superior capsule reconstruction (SCR) and to identify factors related to graft volume change. METHODS: Between May 2018 and June 2021, patients who underwent SCR with acellular dermal matrix allograft for irreparable rotator cuff tear with a minimum 1-year follow-up and who had intact graft continuity in postoperative 6-month magnetic resonance imaging were retrospectively reviewed. The lateral half to the medial half of the graft volume ratio was defined as lateral half graft volume ratio. The difference between the preoperative and postoperative lateral half graft volume ratio was defined as lateral half graft volume change. Patients were divided into 2 groups: those with preserved graft volume (group I) and those with reduced graft volume (group II). Intergroup differences in clinical and radiological characteristics were analyzed. RESULTS: A total of 81 patients were included, with 47 (58.0%) in group I and 34 (42.0%) in group II. Group I showed significantly lower lateral half graft volume change (0.018 ± 0.064 vs 0.370 ± 0.177; P < .001) than group II. Group II showed significantly greater preoperative Hamada grade (1.3 ± 0.5 vs 2.2 ± 0.6, P < .001), an anteroposterior distance of the graft at the greater tuberosity (APGT) (30.3 ± 4.8 vs 35.2 ± 3.8, P < .001), and fatty infiltration of infraspinatus (2.3 ± 0.9 vs 3.1 ± 0.8, P < .001) and subscapularis (0.9 ± 0.9 vs 1.6 ± 1.3, P = .009) than group I. Group II had a significantly lower proportion of patients achieving MIC in Constant score than group I (70.2% vs 47.1%, P = .035). The Hamada grade, APGT, and fatty infiltration of infraspinatus and subscapularis were independent factors of graft volume change. CONCLUSIONS: Although SCR improved pain and shoulder function, postoperative graft volume reduction was related to a lower rate of minimal important change achievement in the Constant score compared with preserved graft volume. The preoperative Hamada grade, APGT, and fatty infiltration of infraspinatus and subscapularis were associated with graft volume reduction. LEVEL OF EVIDENCE: Level III, retrospective case-control study.

No Difference In Clinical Outcomes Following Repair of Large Retracted Anterior Rotator Cuff Tears Using Patch Augmentation With Human Dermal Allograft Versus Anterior Cable Reconstruction With Biceps Tendon Autograft.

PURPOSE: To compare the clinical outcomes and tendon integrity after rotator cuff repair combined with anterior cable reconstruction (ACR) using the proximal biceps tendon and patch augmentation (PA) using a human dermal allograft (HDA) in a large retracted anterior rotator cuff tear. METHODS: Patients who underwent arthroscopic rotator cuff repair with 2 different augmentation procedures between January 2017 and December 2020 were enrolled. The inclusion criteria were patients who were treated by arthroscopic rotator cuff repair with ACR using the proximal biceps tendon (ACR group) or patch augmentation using a an HDA (PA group) and follow-up for at least 2 years. Clinical outcomes were assessed using American Shoulder and Elbow Surgeons (ASES) score, Constant score, and the number of patients who achieved minimal clinically important differences (MCID). Magnetic resonance imaging was performed to evaluate tendon integrity after surgery. RESULTS: A total of 92 patients were enrolled (ACR group = 55 patients and PA group = 37 patients). The mean ASES and Constant scores significantly improved in the ACR group (68.8 ± 15.3 and 58.4 ± 16.9 before surgery vs 91.4 ± 6.3 and 87.8 ± 6.0 after surgery, P < .001) and in the PA group (63.7 ± 16.7 and 57.9 ± 15.4 before surgery vs 93.1 ± 6.3 and 88.3 ± 6.2 after surgery, P < .001). Overall, 78 patients (84.8%) achieved the MCID with 81.8% in the ACR group and 89.2% in the PA group, with no significant differences between the 2 groups (P = .638). Ten patients (18.2%) had retear in the ACR group, and three patients (8.1%) had retear in the PA group (P = .174). CONCLUSIONS: In large retracted anterior rotator cuff tears, both augmentation techniques using biceps tendon autograft and HDA provided satisfactory clinical outcomes that achieved the MCID in 84.8%, range of motion restoration, and lower retear rates with no significant differences between the two groups. LEVEL OF EVIDENCE: Level III, retrospective case-control study.

Occult, Incomplete, and Complete Posterior Labral Tears Without Glenohumeral Instability on Imaging Underestimate Labral Detachment.

PURPOSE: To introduce a classification of posterior labral tear and describe clinical characteristics, magnetic resonance imaging (MRI)/magnetic resonance arthrography (MRA) findings, arthroscopic findings, and outcomes after arthroscopic repair for patients with posterior labral tears without glenohumeral instability. METHODS: Sixty patients with posterior labral tear who underwent arthroscopic repair were analyzed retrospectively. Patients with shoulder instability were excluded. Tear patterns were classified into 3 types; occult (type 1), incomplete (type 2), and complete (type 3) based on MRI/MRA studies. A visual analog scale score for pain, American Shoulder and Elbow Surgeons score, Single Assessment Numeric Evaluation score for satisfaction, and return to sports were evaluated at a minimum follow-up of 2 years. Computed tomography arthrography was performed at a year follow-up for assess labral healing. The diagnosis was confirmed in arthroscopy, and arthroscopic labral repair without capsular plication was performed. RESULTS: The mean patient age was 30.4 ± 6.9 years, and all patients were male. Forty-four patients (73.3%) were participating in sports. MRI/MRA studies identified 10 patients with type 1, 18 with type 2, and 32 with type 3 tears. Type 1 tear patients showed a significantly longer symptom duration than those with type 3 (32.5 ± 17.2 vs 18.2 ± 17.1 months; P = .015). In arthroscopic findings, 70% of type 1 tear was confirmed as incomplete or complete tears. The American Shoulder and Elbow Surgeons score improved from 79.6 ± 10.3 to 98.1 ± 3.7, and pain was relieved from 2.4 ± 0.7 to 0.2 ± 0.5 at the last follow-up visit with high labral healing rate (95%). Thirty-nine (88.6%) patients returned to sports at preinjury levels. CONCLUSIONS: In active young men with shoulder pain during daily activities or sports despite programmed conservative treatment, posterior labral tears should be considered even when MRI/MRA findings are ambiguous. Arthroscopic posterior labral repair without capsular plication provided satisfactory clinical outcomes and a high labral healing rate. LEVEL OF EVIDENCE: Level Ⅳ, case series.

Arthroscopic suprapectoral biceps tenodesis provided earlier shoulder function restoration compared with open subpectoral biceps tenodesis during the recovery phase.

BACKGROUND: This study compared the clinical outcomes of open subpectoral biceps tenodesis and arthroscopic suprapectoral biceps tenodesis for symptomatic biceps tenosynovitis. Although both techniques have pros and cons, no studies have compared clinical and functional outcomes during the recovery phase. Previous studies show that suprapectoral tenodesis has a higher probability of Popeye deformity and postoperative bicipital pain and stiffness, whereas subpectoral tenodesis has a higher risk of nerve complications and wound infections. This study aimed for clinical comparison between arthroscopic suprapectoral biceps tenodesis and open subpectoral biceps tenodesis. METHODS: This study is a retrospective review of institutional records of patients with biceps tendinitis who underwent open or arthroscopic biceps tenodesis. Surgical indications included biceps tenosynovitis, biceps partial tear, and biceps pulley lesion. Patients with prior shoulder surgery, preoperative shoulder stiffness, or full-thickness tear of rotator cuff were excluded. Tenodesis was considered when the pain recurs within 3 months despite conservative treatment including at least 2 triamcinolone injections on the biceps tendon sheath. Visual analog scale (VAS) score for pain, presence of the night pain, American Shoulder and Elbow Surgeons (ASES) score, Constant score, and range of motion were assessed preoperatively at 3, 6, 12, and 24 months postoperatively and the last follow-up. RESULTS: A total of 72 patients (33 with arthroscopic suprapectoral biceps tenodeses and 39 with open subpectoral biceps tenodeses) were included in analysis. At postoperative 6 months, lower VAS score (0.4 ± 0.8 vs. 1.7 ± 1.9, P < .001), and the presence of the night pain (2 [6%] vs. 14 [36%], P = .002), ASES score (89.6 ± 9.2 vs. 81.4 ± 14.6, P = .006), and Constant score (89.4 ± 5.6 vs. 82.0 ± 12.5, P = .003) compared with the subpectoral group. The mean number of postoperative steroid injections for pain control in the subpectoral group (0.51 ± 0.80) was significantly higher than that in the suprapectoral group (0.18 ± 0.40) (P = .031). However, postoperative clinical outcomes were restored similar between the 2 groups at 12 months and the last follow-up. DISCUSSION: Arthroscopic suprapectoral biceps tenodesis performed statistically better than the subpectoral biceps tenodesis for the VAS, ASES, night pain, and Constant score at postoperative 6 months. However, only night pain and the Constant score showed differences that exceeded minimum clinically important difference during the recovery phase. At postoperative 12 and 24 months, biceps tenodesis provided satisfactory clinical outcomes and pain relief regardless of the fixation technique and suture anchor location.

Extracellular Vesicles from Cerebrospinal Fluid of Leptomeningeal Metastasis Patients Deliver MiR-21 and Induce Methotrexate Resistance in Lung Cancer Cells.

Leptomeningeal metastasis (LM) is a common and fatal complication of advanced non-small cell lung cancer (NSCLC) caused by the spread of malignant cells to the leptomeninges and cerebrospinal fluid (CSF). While intra-CSF methotrexate (MTX) chemotherapy can improve prognosis, eventual MTX resistance deters continued chemotherapy. Recent studies have shown that increased miRNA-21 (miR-21) expression in the CSF of patients with LM after intraventricular MTX-chemotherapy is associated with poor overall survival; however, the molecular mechanisms underlying this resistance are poorly understood. Here, we confirm, in 36 patients with NSCLC-LM, that elevated miR-21 expression prior to treatment correlates with poor prognosis. MiR-21 overexpression or sponging results in a corresponding increase or decrease in MTX resistance, demonstrating that cellular miR-21 expression correlates with drug resistance. MiR-21-monitoring sensor and fluorescent extracellular vesicle (EV) staining revealed that EV-mediated delivery of miR-21 could modulate MTX resistance. Moreover, EVs isolated from the CSF of LM patients containing miR-21 could enhance the cell proliferation and MTX resistance of recipient cells. These results indicate that miR-21 can be transferred from cell-to-cell via EVs and potentially modulate MTX sensitivity, suggesting that miR-21 in CSF EVs may be a prognostic and therapeutic target for overcoming MTX resistance in patients with NSCLC-LM.

Radiological safety assessment for transportation of reactor pressure vessel during decommissioning of a nuclear power plant in Korea.

In Korea, decommissioning of nuclear power plants and transportation of the decommissioning waste are expected to expand in the near future. It is necessary to confirm that radiological risks to the public and workers are not significant through radiological safety assessment. The objective of this study is to assess the radiological safety for transportation of RPV waste, which is a major decommissioning waste with relatively high level of radioactivity. It was assumed that the waste would be transported to the Gyeongju disposal facility by land transportation. First, the source term and transportation method of the RPV waste were determined, and the external dose rates from the waste were calculated using MCNP. Then, transportation scenarios were assumed under both normal and accident conditions. Under the scenarios, radiation doses were calculated using the RADTRAN. Under normal operation scenarios without a transportation accident, assuming 40 shipments per year, the average individual doses for the public ranged from 6.56×10-6to 2.18×10-2mSv yr-1. The maximum individual doses for only a single shipment ranged from 2.43×10-6to 3.14×10-1mSv. For cargo handlers and vehicle crew members, the average doses were 2.26×101mSv yr-1and 2.95 mSv yr-1, respectively. Under transportation accident scenarios, average individual radiological risks which are product of the radiation doses and the annual accident rates ranged from 1.14×10-11to 1.61×10-10mSv yr-1by transportation route segment when considering the transportation accident rate. Average individual doses assuming transportation accident occurrence ranged from 2.62×10-4to 1.42×10-3mSv. The maximum individual dose under accident conditions was 7.99×10-2mSv. The calculated doses were below the regulatory limits in Korea. However, relatively high doses were observed for cargo handlers and vehicle crew members because of conservative assumptions. This study results can be used as basic data for the radiological safety assessment for the decommissioning waste transportation in the future.