Skeletal muscle atrophy is a major complication associated with aging, chronic disease, and chemotherapy. Doxorubicin (Dox), a widely used anticancer agent, accelerates muscle wasting; however, the underlying cellular mechanisms remain poorly understood. In this study, we examined the effects of Dox on myogenic differentiation, senescence, and lipid metabolism using C2C12 myoblasts. Dox exposure impaired myotube formation without causing overt cytotoxicity. Mechanistically, Dox disrupted myogenic differentiation by inhibiting protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling, thereby de-repressing forkhead box O1/3 (FOXO1/3) and upregulating the muscle-specific ubiquitin ligases muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1), which promote proteolysis. Dox also decreased glycogen synthase kinase 3β (GSK3β) phosphorylation while paradoxically increasing total and phosphorylated β-catenin, indicating dysregulated Wnt/β-catenin signaling. These alterations were accompanied by a senescence-like phenotype, characterized by elevated senescence-associated β-galactosidase (SA-β-gal) activity, increased phosphorylated histone variant γH2AX, and activation of the p53–p21 axis. Notably, cellular senescence coincided with excessive lipid accumulation in myotubes. Dox reduced phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) while enhancing expression of key lipogenic regulators, thereby creating a metabolic environment favoring lipid storage. Collectively, these findings demonstrate that Dox not only suppresses myogenic differentiation but also induces premature senescence and metabolic reprogramming toward lipid accumulation. Targeting these pathways through AMPK activation, FOXO inhibition, or senolytic interventions may offer therapeutic strategies to preserve skeletal muscle integrity in patients undergoing chemotherapy.

Background/Aims: Biliary tract cancer (BTC) is a rare malignancy with poor prognosis. We investigated genomic determinants of clinical benefit from gemcitabine, cisplatin, and nab-paclitaxel (GAP) versus gemcitabine and cisplatin (GC) in advanced BTC. Methods: Clinical and genomic data using TruSight Oncology 500 were analyzed from patients treated with GAP (N=198) or GC (N=89) as first-line therapy. Results: With a median follow-up of 33.0 months, GAP modestly improved progression-free survival (PFS) (hazard ratio [HR] 0.764; 95% confidence interval [CI] 0.591–0.989) without significant overall survival (OS) difference compared to GC. Genomic profiling revealed frequent alterations in TP53 (35.2%), KRAS (16.4%), SMAD4 (10.5%), and TNFRSF14 (10.5%), involving RTK/RAS (44.3%), TP53 (41.8%), and PI3K (20.2%) pathways. Single-gene mutations did not predict treatment benefit. However, pathway-level analysis identified PI3K pathway activation as significantly associated with inferior PFS (HR 2.148; 95% CI 1.478–3.124) and OS (HR 2.096; 95% CI 1.413–3.109) in patients receiving GAP, an effect not observed with GC. Importantly, GAP conferred clinical benefit only in patients without PI3K pathway activation, while no survival advantage was seen in those with such alterations (Pinteraction=0.023 for PFS, Pinteraction=0.003 for OS). Similar results were obtained in the independent validation cohort treated with GAP (N=103) or GC (N=64) for BTC. Conclusions Genomic profiling using next-generation sequencing identified PI3K pathway activation as key molecular determinant that differentiates patient outcomes between GAP and GC treatments in advanced BTC.

Objective: Youths with disruptive behavior disorders (DBDs) and a history of trauma exposure often exhibit deficits in neural mechanisms related to reward anticipation and assessment. This preliminary investigation examines the potential of a serotonergic agent (fluoxetine) to modulate neural activity in reward-related pathways for this population. Methods: Three participant groups were: (i) youth with DBDs and trauma exposure who received fluoxetine treatment for 8 weeks (n = 12); (ii) a matched group of youth with DBDs and trauma exposure who received routine regular followup in an outpatient clinic (n = 9); and (iii) typically developing youth (n = 19). All participants completed a passive avoidance fMRI task twice, 8 weeks apart (pre-treatment and post treatment for youth with DBDs). Results: Youth with DBDs and trauma exposure who received fluoxetine treatment compared to the other two groups showed: (i) significant improvement in externalizing, oppositional defiant disorder, irritability, anxiety-depression, and trauma-related symptoms; (ii) significantly increased recruitment of regions implicated in reward expectation (e.g., ventral tegmental area, nucleus accumbens), monitoring prediction error (e.g., dorsolateral prefrontal cortex, posterior parietal cortex), and inhibitory control (e.g., anterior insula, pre-supplementary motor area, anterior prefrontal cortex. Conclusion We provide preliminary data suggesting that a serotonergic medication can correct reward processing and provide symptom improvement in youth with DBDs and a history of trauma exposure. Given the small sample size, more rigorous studies with larger sample size are needed to confirm these results. The findings of this study could aid future clinical research and treatment for this challenging population.

Objective: Primary frozen shoulder causes significant pain and progressively restricts shoulder movements. Diagnosis is made clinically based on patient history and physical examination. Management is mainly non-invasive owing to its self-limiting clinical course. However, clinical practice guidelines for frozen shoulder have not yet been developed in Korea. The developed guidelines aim to provide evidence-based recommendations for the diagnosis and treatment of frozen shoulder. Methods: A guideline development committee reviewed the literature from four databases (PubMed, Embase, Cochrane Library, and KMbase). Using the Population, Intervention, Comparator, and Outcome (PICO) framework, the committee formulated two backgrounds and 16 key questions to address common clinical concerns. Recommendations were made using the Grading of Recommendations, Assessment, Development, and Evaluation framework. Results: Diabetes, thyroid disease, and dyslipidemia significantly increase the risk of developing a frozen shoulder. Although frozen shoulder is often self-limiting, some patients may experience long-term functional disabilities. Ultrasound and magnetic resonance imaging should be used as adjunctive tools alongside clinical diagnosis, and rather than as independent diagnostic methods. Noninvasive approaches, such as medications, physical modalities, exercises, electrical stimulation, and manual therapy, may reduce pain and improve shoulder function. Other noninvasive interventions have limited evidence, and their application should be based on clinical judgment. Intra-articular steroid injections are recommended for treatment, and physiotherapy or hydrodilation with steroid injections can also be beneficial. Conclusion These guidelines provide evidence-based recommendations for diagnosing and treating primary frozen shoulder.

Purpose: Incidental prostate cancer (IPCa) is frequently discovered during radical cystectomy (RC) for bladder cancer. While small-scale Korean studies have reported IPCa in 36%–50% of cases and clinically significant prostate cancer (sPCa) in up to 20%, large-scale data assessing its oncologic impact remain scarce. Materials and Methods: We retrospectively analyzed 1,358 male patients who underwent RC between June 1996 and January 2024. IPCa was histologically confirmed and classified per the International Society of Urological Pathology (ISUP) system. sPCa was defined as ISUP grade group (GG) ≥2. Kaplan-Meier analyses were conducted to evaluate survival outcomes. Results: IPCa was identified in 240 patients (17.7%), among whom 7.51% had sPCa. The distribution of ISUP GG was: GG1, 53.8%; GG2, 27.9%; GG3, 9.6%; GG4, 2.5%; and GG5, 1.7%. The proportion of sPCa remained stable across 3 time periods (p=0.281). Mean preoperative prostate-specific antigen (PSA) levels significantly differed among GG1, GG2, and GG3+ groups (2.14±2.37, 4.31±6.69, and 5.86±7.66 ng/mL, respectively; p<0.001). Mean patient age also varied significantly (67.99±8.39, 71.54±8.60, and 72.97±5.53 years; p<0.001). After a median follow-up of 44 months, deaths were unrelated to IPCa. Biochemical recurrence (BCR), defined as PSA ≥0.2 ng/mL, occurred in 11 patients (4.58%), with rates of 3.10%, 4.48%, and 12.12% in GG1, GG2, and GG3+ groups, respectively. Overall mortality rates across GG groups were similar (33.3%, 34.3%, and 33.3%; p=0.99). Compared to GG1, hazard ratios for overall survival were 1.03 (GG2, p=0.92), 0.87 (GG3, p=0.76), and 1.05 (GG4–5, p=0.89). Conclusion In this large Korean cohort, IPCa and sPCa were frequently detected at rates similar to global reports. Bladder cancer remained the primary determinant of survival. For older patients with elevated PSA, radical cystoprostatectomy may offer added benefit by treating undiagnosed high-risk IPCa.

Objective: To evaluate the outcomes of drug-eluting bead transarterial chemoembolization (DEB-TACE) according to the size of the beads for the treatment of small hepatocellular carcinoma (HCC). Materials and Methods: This retrospective study included 212 patients with a single HCC ≤5 cm from five tertiary institutions. One hundred and nine patients were treated with 70–150-µm doxorubicin DEBs (group A), and 103 patients received 100–300-µm doxorubicin DEBs (group B). The initial tumor response (assessed between 3 weeks and 2 months after DEB-TACE), time to local tumor progression (TTLTP), restricted mean duration of complete response (RMDCR), rate of complications, incidence of post-embolization syndrome, and length of hospital stay were compared between the two groups.Logistic regression was used to analyze prognostic factors for initial tumor response. Results: The initial objective response rates were 91.7% (100/109) and 84.5% (87/103) for groups A and B, respectively (P = 0.101). In the subgroup analysis of tumors ≤3 cm, the initial objective response rates were 94.6% (53/56) and 78.0% (39/50) for groups A and B, respectively (P = 0.012). There was no significant difference in the TTLTP (median, 23.7 months for group A vs. 19.0 months for group B; P = 0.278 [log-rank], 0.190 [multivariable Cox regression]) or RMDCR at 24 months (11.4 months vs. 8.5 months, respectively; P = 0.088). In the subgroup analysis of tumors >3-cm, the RMDCR at 24 months was significantly longer in group A than in group B (11.8 months vs. 5.7 months, P = 0.024). The incidence of mild bile duct dilatation after DEB-TACE was significantly higher in group B than in group A (5.5% [6/109] vs. 18.4% [19/103], P = 0.003). Conclusion DEB-TACE using 70–150-µm microspheres demonstrated a higher initial objective response rate in ≤3-cm HCCs and a longer RMDCR at 24 months in 3.1–5-cm HCCs compared to larger DEBs (100–300-μm).

Background: s/Aims: Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021. Methods: Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop. Results: In November 2021, the finalized draft was presented for public scrutiny during a formal hearing. Conclusions The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.

The facial nerve stimulates the muscles of facial expression and the parasympathetic nerves of the face. Consequently, facial nerve paralysis can lead to facial asymmetry, deformation, and functional impairment. Facial nerve palsy is most commonly idiopathic, as with Bell palsy, but it can also result from a tumor or trauma. In this article, we discuss traumatic facial nerve injury. To identify the cause of the injury, it is important to first determine its location. The location and extent of the damage inform the treatment method, with options including primary repair, nerve graft, cross-face nerve graft, nerve crossover, and muscle transfer. Intracranial proximal facial nerve injuries present a challenge to surgical approaches due to the complexity of the temporal bone. Surgical intervention in these cases requires a collaborative approach between neurosurgery and otolaryngology, and nerve repair or grafting is difficult. This article describes the treatment of peripheral facial nerve injury. Primary repair generally offers the best prognosis. If primary repair is not feasible within 6 months of injury, nerve grafting should be attempted, and if more than 12 months have elapsed, functional muscle transfer should be performed. If the affected nerve cannot be utilized at that time, the contralateral facial nerve, ipsilateral masseter nerve, or hypoglossal nerve can serve as the donor nerve. Other accompanying symptoms, such as lagophthalmos or midface ptosis, must also be considered for the successful treatment of facial nerve injury.

Background: Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined. Methods: This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months. Conclusion This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Background/Aims: Palliative chemotherapy (PC) is not standardized for patients with advanced ampulla of Vater adenocarcinoma (AA). This multicenter, retrospective study evaluated first-line PC outcomes in patients with AA. Methods: Patients diagnosed with AA between January 2010 and December 2020 who underwent PC were enrolled from 10 institutions. Overall survival (OS) and progression-free survival (PFS) according to the chemotherapy regimen were analyzed. Results: Of 255 patients (mean age, 64.0±10.0 years; male, 57.6%), 14 (5.5%) had locally advanced AA and 241 (94.5%) had metastatic AA. Gemcitabine plus cisplatin (GP) was administered as first-line chemotherapy to 192 patients (75.3%), whereas capecitabine plus oxaliplatin (CAPOX) was administered to 39 patients (15.3%). The median OS of all patients was 19.8 months (95% confidence interval [CI], 17.3 to 22.3), and that of patients who received GP and CAPOX was 20.4 months (95% CI, 17.2 to 23.6) and 16.0 months (95% CI, 11.2 to 20.7), respectively. The median PFS of GP and CAPOX patients were 8.4 months (95% CI, 7.1 to 9.7) and 5.1 months (95% CI, 2.5 to 7.8), respectively. PC for AA demonstrated improved median outcomes in both OS and PFS compared to conventional bile duct cancers that included AA. Conclusions While previous studies have shown mixed prognostic outcomes when AA was analyzed together with other biliary tract cancers, our study unveils a distinct clinical prognosis specific to AA on a large scale with systemic anticancer therapy. These findings suggest that AA is a distinct type of tumor, different from other biliary tract cancers, and AA itself could be expected to have a favorable response to PC.