Second-Line Fluoropyrimidine-Based Chemotherapy in Advanced Biliary Tract Cancer: A Meta-Analysis Based on Individual Patient-Level Data of Randomized Trials.

PURPOSE: While fluoropyrimidine-based chemotherapy regimens are recommended second-line treatment for patients with advanced biliary tract cancer (BTC), there have been no studies comparing different regimens head-to-head. MATERIALS AND METHODS: We performed individual patient-level meta-analysis based on data from the intention-to-treat population of the phase 2b NIFTY trial (liposomal irinotecan [nal-IRI] plus fluorouracil and leucovorin [5-FU/LV] vs. 5-FU/LV; NCT03542508) and the phase 2 FIReFOX trial (modified oxaliplatin plus 5-FU/LV [mFOLFOX] vs. modified irinotecan plus 5-FU/LV [mFOLFIRI]; NCT03464968). Pairwise log-rank tests and multivariable analysis using Cox proportional hazards modeling with shared frailty to account for the trial's effect were used to compare overall survival (OS) between regimens. RESULTS: A total of 277 patients were included. The nal-IRI plus 5-FU/LV group (n=88) showed significantly better OS compared to the mFOLFOX group (n=49, pairwise log-rank, p=0.02), and mFOLFIRI group (n=50, p =0.03). Multivariable analysis showed consistent trends in OS with adjusted hazard ratios of 1.39 (mFOLFOX vs nal-IRI plus 5-FU/LV, 95% CI 0.93-2.07, p=0.11) and 1.36 (mFOLFIRI vs nal-IRI plus 5-FU/LV, 95% CI 0.92-2.03, p=0.13), respectively. Compared to the 5-FU/LV group, the mFOLFOX group and the mFOLFIRI group did not show differences in terms of OS (pairwise log-rank p=0.83 and p=0.58, respectively). The nal-IRI plus 5-FU/LV group experienced more frequent diarrhea, while the mFOLFOX group experienced peripheral neuropathy. CONCLUSION: Nal-IRI plus 5-FU/LV showed favorable survival outcomes compared to mFOLFOX, mFOLFIRI, or 5-FU/LV. The safety profiles of these regimens should be considered along with efficacy.

Long-term clinical outcomes after the second metastasectomy in patients with resected metastatic colorectal cancer.

PURPOSE: Primary tumor resection and metastasectomy are curative for metastatic colorectal cancer. However, there is still a paucity of data regarding the clinical outcomes and risk factors after disease recurrence and second metastasectomy. MATERIALS AND METHODS: We retrospectively evaluated the clinical outcomes of patients who underwent the second metastasectomy. In addition, risk factors for the outcomes were analyzed. RESULTS: A total of 94 patients (39 females and 55 males) received a second metastasectomy after the recurrence. Recurrent sites included the lung (47 patients), liver (36 patients), both lung and liver (four patients), and non-lung/non-liver (seven patients). Among them, 89 (94.7 %) patients achieved R0 resection, while three (3.2 %) and two (2.1 %) patients achieved R1 and R2 resections, respectively. The 5-year disease-free survival (DFS) and overall survival (OS) were 42.8±5.3 % and 67.2±4.9 %, respectively. Multivariable analysis for DFS identified that primary rectal cancer (hazard ratio [HR] 0.45, P=0.033) and disease-free interval after the first metastasectomy of ≥12 months (HR 0.39, P=0.002) were good predictive factors; in contrast, non-lung/non-liver metastasis (HR 3.32, P=0.020) was a poor predictive factor. Multivariable analysis for OS showed that age ≥70 years (HR 3.27, P=0.011), non-lung/non-liver metastasis (HR 4.04, P=0.024), and lesion number ≥2 (HR 2.25, P=0.023) were poor prognostic factors. CONCLUSION: Patients who underwent a second metastasectomy had a long-term disease-free state and good OS. Our data suggest that a second metastasectomy should be considered if a patient has a limited number of metastases confined to the liver and/or lung and long DFS after the first metastasectomy.

Effectiveness of Early Thiopurine Use in Korean Patients With Moderate-to-Severe Ulcerative Colitis: A Prospective Multicenter Cohort (MOSAIK) Study.

BACKGROUND: Thiopurines play an important role in the management of steroid-refractory and steroid-dependent ulcerative colitis. However, the effectiveness of the early use of thiopurines in ulcerative colitis remains controversial. MATERIALS AND METHODS: In this multicenter prospective cohort (MOSAIK) study, we divided patients with ulcerative colitis into those who underwent early (within 6 mo of diagnosis) and late (6 mo after diagnosis) thiopurine therapy to determine the effectiveness of early thiopurine treatment. The primary outcome was the cumulative rate of clinical relapse (Mayo score >2 points). Multivariate Cox proportional hazards regression was used to identify independent clinical factors associated with the outcomes. RESULTS: Overall, 333 patients with moderate-to-severe ulcerative colitis were included. Of the 118 patients treated with thiopurines, 65 (55.1%) and 53 (44.9%) received thiopurine therapy within and after 6 months of diagnosis. The cumulative use rate of thiopurines was 38.9% at 3 years after diagnosis. The median initial dose of thiopurines was 0.7 mg/kg (0.3 to 2.0); the median maintenance dose was 1.1 mg/kg (0.3 to 2.4). The cumulative rate of clinical relapse was not significantly different between patients who started thiopurine therapy within 6 months of diagnosis and those who started therapy 6 months after diagnosis (P=0.712). The presence of extraintestinal manifestations (hazard ratio: 4.674, 95% CI: 1.210-18.061, P=0.025) independently predicted an increased risk of clinical relapse. CONCLUSIONS: Patients with ulcerative colitis who received early thiopurine therapy did not differ significantly in terms of clinical relapse compared with those who received late therapy.

Cumulative impact of hypotension during intermittent hemodialysis on kidney recovery in critically ill patients with AKI-D.

BACKGROUND: Intermittent hemodialysis (IHD) is commonly implemented in patients with AKI-D, irrespective of the initial kidney replacement therapy (KRT) modality. However, concerns remain regarding the hemodynamic instability during IHD. This study aimed to assess the association between hypotensive episodes during IHD and kidney recovery in AKI-D patients. METHODS: We retrospectively enrolled AKI-D survivors who received IHD in the intensive care units of a tertiary care hospital in Korea from January 2018 to February 2024. RESULTS: A total of 1791 IHD sessions from 209 AKI-D survivors were analyzed. The patients underwent a median of 7 IHD sessions (interquartile range [IQR] 3-11), with an incidence of intradialytic hypotension (IDH) of 16.8 % per patient. Of these, 43.1 % were dialysis-dependent at hospital discharge. The number of IDH was a significant predictor of dialysis dependence (odds ratio [OR] 1.56; 95 % confidence interval [CI] 1.16-2.22). Patients experiencing ≥3 IDH episodes had a substantially higher risk of dialysis dependence compared to those without IDH (OR 9.41; 95 % CI 2.41-41.69). In per-session analysis, the target ultrafiltration rate was identified as an independent risk factor for IDH occurrence. CONCLUSIONS: Our study revealed that IHD-related hypotension during hospitalization has a cumulative negative impact on kidney recovery in AKI-D survivors.

Clinical significance of gross extrathyroidal extension to only the strap muscle according to tumor size in differentiated thyroid cancer: a systematic review and metaanalysis.

Objective: The presence of extrathyroidal extension (ETE) in differentiated thyroid cancer (DTC) patients is an important predictor of their prognosis. Therefore, the tumor stage of DTC is divided into extensive ETE and gross ETE only affecting the strap muscle (Gross strap muscles invasion; gSMI). However, insufficient evidence exists regarding the association of gSMI with the prognosis, especially in relation to tumor size. Methods: Related literature was searched in MEDLINE, Embase, Cochrane Library and KoreaMed. All processes were performed in accordance with PRISMA guidelines, and the process was conducted by two independent reviewers. The meta-analysis was performed using a random-effect model considering the diversity of studies. RoBANS version 2.0, an evaluation tool for non-randomized studies, was used to evaluate the quality of the selected research. Clinical data from observational studies that analyzed the relationship between the degree of ETE and prognosis were collected, and a meta-analysis was performed. Results: Eighteen observational studies were included in this study. A subgroup analysis was performed for each outcome. The recurrence rate (odds ratio [OR]: 2.498), disease-specific mortality (risk ratio [RR]: 2.984), overall mortality (RR: 1.361) and lymph node (LN) metastasis (OR: 5.355) were significantly higher in patients with gSMI than in those with no ETE. However, in an analysis limited to tumors 4 cm or smaller, no significant difference in prognostic outcomes was seen, except for LN metastasis. Conclusion: gSMI has a negative impact on the prognosis; however, this correlation diminishes when the tumor size is small. Thus, a more cautious approach is warranted during the treatment process.

Protective effect of Korean red ginseng water extract on levothyroxine-induced hyperthyroidism and propylthiouracil-induced hypothyroidism in rats.

Background: Korean red ginseng extract (KRGE) (Family: Araliaceae) is one of the most widely used traditional herbs in Asia. Multiple studies have shown that KRGE has anti-inflammation, anti-fatigue, anti-obesity, anti-oxidant, and anti-cancer effects. Methods: Sprague-Dawley rats were divided into five groups for PTU-induced hypothyroidism and six groups for LT4-induced hyperthyroidism. At the experiment's conclusion, rats were sacrificed, and blood, thyroid gland, and liver samples were collected. Body weight was recorded weekly, and serum hormone levels were assessed using enzyme-linked immunoassay. Thyroid gland and liver tissues were stained with hematoxylin and eosin. KRGE was prepared in 0.5% CMC and stored at 4 °C before administration. Results: In the LT4-induced hyperthyroidism model, KRGE prevented decreases in body weight, thyroid gland weight, liver weight, serum glucose, and thyroid hormone levels compared to the PTU group. It also reduced increases in T3, T4, and serum aspartate aminotransferase levels after LT4 treatment. Additionally, KRGE improved thyroid gland and liver histopathology, effects not observed in the PTU-induced hypothyroidism model. Conclusion: All things considered, our research points to KRGE's potential protective role in rat hyperthyroidism caused by LT4 by lowering thyroid hormone production.

Development and validation of next-generation sequencing panel for personalized Helicobacter pylori eradication treatment targeting multiple species.

Introduction: The decreasing Helicobacter pylori eradication rate is primarily attributed to antibiotic resistance, and further exacerbated by uniform drug administration disregarding a host's metabolic capability. Consequently, applying personalized treatment based on antibiotic resistance-associated variants and the host's metabolic phenotype can potentially increase the eradication rate. Method: A custom next-generation sequencing panel for personalized H. pylori eradication treatment (NGS-PHET) was designed which targeted the regions for amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin-resistance in H. pylori and human proton-pump inhibitor (PPI) metabolism. The libraries were constructed following customized methods and sequenced simultaneously. The customized framework criteria, grounded in previously reported antibiotic resistance associated variants and the host's PPI metabolism, was applied to the NGS-PHET results and suggested a personalized treatment for each subject, which was validated through each subject's actual eradication outcome. Results: Both previously reported and novel variants were identified from H. pylori sequencing results. Concurrently, five CYP2C19 homozygous extensive metabolizers and three CYP3A4 intermediate metabolizers were identified. Among the total of 12 subjects, clarithromycin triple therapy was suggested for five subjects, bismuth quadruple therapy was suggested for six subjects, and rifabutin triple therapy was suggested for one subject by following the customized framework criteria. The treatment suggestion for nine of the 12 subjects was consistent with the treatment that each subject achieved eradication with. Discussion: Applying the methodology using the NGS-PHET and customized framework helps to perform eradication treatment quickly and effectively in most patients with antibiotic-resistant H. pylori strains, and is also useful in research to find novel antibiotic-resistance candidates.

Radiofrequency ablation with sine and square electrical waveforms to enhance ablation range.

Radiofrequency ablation (RFA) is a local treatment modality for primary liver cancers. Although various input parameters of the RF generator have been adjusted to improve the ablation ranges, the limited ablation ranges remain an obstacle to RFA. This study aimed to compare the ablation ranges and efficacy of sine and square electrical waveforms in a mouse tumor model. An RF generator with an adjustable electrical waveform was developed, and its ablation range in the porcine liver was compared. For all RF parameters, the square electrical waveform ablation range was greater than that of the sine electrical waveform (all p < 0.001) in the porcine liver. The 45 BALB/c nude mice were used to evaluate the efficacy of the two electrical waveforms after the RFA. The mean tumor volume in the square group was significantly lower than that in the sine group (p < 0.001), indicating a higher survival rate (60%). The cellular coagulative necrosis, inflammatory cell infiltration, heat shock proteins, cellular necrosis, and tumor necrosis were significantly greater in square electrical waveform than in sine electrical waveform (all; p < 0.05). RFA with square electrical waveforms has therapeutic potential for tumor management with an enhanced ablation range.

Association between TGF-ß/BMP signaling pathway polymorphisms and the risk of primary ovarian insufficiency in Korean women.

BACKGROUND: Primary ovarian insufficiency (POI) is one of the leading female infertility diseases in which ovarian function stops before the age of 40. Reports that POI is associated with transforming growth factor (TGF)-ß/bone morphogenetic protein (BMP) signaling pathway-associated genes (e.g., TGF-ß, and BMP15) have been continuous since publication that the TGF-ß superfamily acts as important regulators for ovary and placenta function in humans. Mechanistically, the secretion of follicle-stimulating hormone, progesterone, and estrogen is affected by the TGF-ß superfamily in granulosa cells, which are involved in the development of theca cells, oocytes, and granulosa cells. OBJECTIVE: This study aimed to identify the association between genes related to the TGF-ß/BMP signaling pathway and the risk of POI pathogenesis. METHODS: Possible associations between six gene polymorphisms and POI susceptibility were examined in 139 patients with POI and 345 control subjects. RESULTS: Allele combination of TGFBR1 rs334348 G > A and TGFBR3 rs1805110G > A exhibited association with decreased POI risk (adjusted odds ratio [AOR] = 0.165; 95% confidence interval [CI] 0.032-0.847; P = 0.031). Also, TGFBR1 rs1590 G > T and rs334348 G > A and TGFBR3 rs1805110 G > A allele combination exhibited association with decreased POI risk (OR = 0.553; 95% CI 0.374-0.816; P = 0.003). CONCLUSION: This study suggests that polymorphisms in the TGF-ß signaling pathway genes can be useful biomarkers for POI diagnosis and treatment.

Comparison of Franseen and novel tricore needles for endoscopic ultrasound-guided fine-needle biopsy in a porcine liver model.

Endoscopic ultrasound-guided fine needle biopsy is an effective method for obtaining tissue samples from various organs; however, challenges such as inadequate specimens persist. This study compared a newly designed Tricore needle with a Franseen needle for endoscopic ultrasound-guided fine needle biopsy of porcine liver. Both needles were tested on four male Yorkshire pigs. Specimens were obtained with an 100% (36/36) success rate with no procedure-related adverse effects. The Tricore needle experienced significantly less resistance during puncture than Franseen needle (3.83 vs. 5.97 N, P < 0.001) and better ultrasound visibility (168.97 vs. 125.04, P = 0.004). The Tricore needle also achieved faster specimen acquisition time (48.94 vs. 59.90 s, P = 0.038), larger total specimen area (6.67 vs. 4.68 mm2, P = 0.049), fewer fragments (23.94 vs. 31.94, P = 0.190), lager fragment area (0.28 vs. 0.15 mm2, P < 0.001), and more the number of complete portal tracts (15.44 vs. 9.33, P = 0.017) compared to the Franseen needle. The newly designed Tricore needle showed enhanced procedural performance and specimen quantity and quality compared to commercially available Franseen needle. Although further clinical studies are required, the Tricore needle may represent a favorable option for endoscopic ultrasound-guided fine-needle biopsy procedures.

Interleukin-37 Inhibits Interleukin-1ß-Induced Articular Chondrocyte Apoptosis by Suppressing Reactive Oxygen Species.

Objective: Chondrocyte apoptosis has been considered a crucial mechanism that is responsible for cartilage destruction in osteoarthritis (OA). The mechanism of interleukin-37 (IL-37) on chondrocyte apoptosis has not been clearly determined in the pathogenesis of OA. Here, we explored the role of IL-37 in the regulation of cellular apoptosis in rat chondrocytes stimulated by IL-1ß. Methods: Rat chondrocytes were used in in vitro study, and were stimulated with IL-1ß (10 ng/mL) and/or recombinant IL-37 (rIL-37; 100 ng/mL) after cytotoxicity assessments using these cytokines were conducted. After rIL-37 treatment of chondrocytes stimulated with IL-1ß, the cell proliferation assay, apoptosis assays, including expression of mitochondrial apoptosis-related markers, flow cytometry analysis of annexin V-FITC/propidium iodide (PI), cell cycle analysis, and Hoechst 33342 staining, and reactive oxygen species (ROS) measurement were used. Results: IL-1ß induced expression of inflammatory cytokines and triggered degradation of the extracellular matrix of rat chondrocytes, but this effect was significantly attenuated by rIL-37 treatment. Enhanced ROS generation following IL-1ß stimulation was reduced in a dose-dependent manner after stimulation with rIL-37. IL-1ß induced pro-apoptotic markers and suppressed anti-apoptotic markers in rat chondrocytes. Flow cytometry using annexin V-FITC/PI revealed that IL-1ß increased the apoptosis rate of rat chondrocytes, and that this effect was markedly reversed by treatment with rIL-37. Conclusions: IL-37 potently attenuated IL-1ß-mediated apoptosis of rat chondrocytes by blocking ROS production. This study suggests that IL-37 can serve as a novel anti-cytokine therapy in OA by blocking chondrocyte apoptosis.

The Role of Direct Oral Anticoagulants in Managing Myeloproliferative Neoplasms Patients.

Purpose: Thrombosis and bleeding significantly affect morbidity and mortality in myeloproliferative neoplasms (MPNs). The efficacy and safety of direct oral anticoagulants (DOACs) in MPN patients remain uncertain. Materials and Methods: We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service database from 2010 to 2021. Results: Out of the 368 MPN patients included in the final analysis, 62.8% were treated with DOACs for atrial fibrillation (AF), and 37.2% for venous thromboembolism (VTE). The AF group was statistically older with higher CHA2DS2-VASc scores compared to the VTE group. Antiplatelet agents were used in 51.1% of cases, and cytoreductive drugs in 79.3%, with hydroxyurea being the most common (64.9%). The median follow-up was 22.3 months, with one-year cumulative incidence rates of thrombosis and bleeding at 11.1% and 3.7%, respectively. Multivariate analysis identified CHA2DS2-VASc scores ≥ 3 (HR=3.48), concomitant antiplatelet use (HR = 2.57), and cytoreduction (HR=2.20) as significant thrombosis risk factors but found no significant predictors for major bleeding. Conclusion: Despite the limitations of retrospective data, DOAC treatment in MPN patients seems effective and has an acceptable bleeding risk.

Clinicians' Prediction of Survival Is Most Useful for Palliative Care Referral.

Background: Timely palliative transition in patients with advanced cancer is essential for their improved quality of life and overall survival (OS). Most prognostic models have been developed focusing on weeks' survival. The current study aimed to compare the accuracies of several indicators, such as the Karnofsky Performance Scale (KPS), Clinicians' Prediction of Survival (CPS), and Edmonton Symptom Assessment System (ESAS), for predicting the survival of patients. Methods: Two hundred patients were enrolled at a single tertiary cancer center in South Korea between 2016 and 2019. We compared the discrimination of CPS versus KPS and ESAS total scores using the area under the receiver operating characteristic curve (AUROC) in 3-month and 6-month survival predictions. Results: The median age of patients was 66.0 years, and 128 (64%) were male. Two-thirds (66%) of the patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 55.5% had a KPS of 80% or higher. The values of AUROC of CPS, KPS, and ESAS total score in 3-month survival prediction were 0.80 (95% confidence interval [CI]: 0.73-0.88), 0.71 (95% CI: 0.62-0.79), and 0.71 (95% CI: 0.62-0.81), respectively, whereas those in 6-month survival were 0.82 (95% CI: 0.76-0.88), 0.70 (95% CI: 0.63-0.78), and 0.63 (95% CI: 0.55-0.71), respectively. Conclusion: CPS showed the highest accuracy in predicting 3- and 6-month survival, whereas KPS had an acceptable accuracy. Experienced clinicians can rely on CPS to predict survival in months. We recommend the use of KPS with CPS to assist inexperienced clinicians.

Role of induction chemotherapy in advanced-stage olfactory neuroblastoma.

OBJECTIVES: To evaluate the treatment outcomes in patients with advanced-stage olfactory neuroblastoma (ONB) who received induction chemotherapy (IC). MATERIALS AND METHODS: The clinical data of 38 patients with advanced-stage ONB who received initial IC were retrospectively analyzed. The response was defined using the Response Evaluation Criteria in Solid Tumors version 1.1. Patients with complete remission or partial remission were defined as responders. RESULTS: Seventeen (44.7%) patients responded to IC. The response rate was higher in patients with high Hyams grade tumor (III/IV) compared to those with low-grade tumors (I/II) (60% vs. 22.2%, p = 0.038). Overall, the 5-year cancer-specific survival (CSS) rate was 76.0%. Among nonresponders to IC, a significant difference in 5-year CSS rates was observed between surgery with adjuvant radiotherapy (RT) (100%) versus definitive RT or chemoradiotherapy (CRT) (68.6%) (log-rank p = 0.006). However, for responders, there was no significant difference in 5-year CSS rates between surgery with adjuvant therapy (75%) and definitive RT or CRT (51.1%) (log-rank p = 0.536). When only high-grade tumors were considered among responders, the 5-year CSS rate was significantly higher in patients who received RT or CRT (51.4%) compared to those who underwent surgery with adjuvant therapy (0%) (log-rank p = 0.008). CONCLUSION: In advanced-stage ONB, RT or CRT may be preferable for high-grade tumor responding to IC. Higher response rate and a potential role for induction IC in determining the optimal definitive treatment modality suggest a positive role for advanced-stage high-grade ONB.

Biophysically stressed vascular smooth muscle cells express MCP-1 via a PDGFR-ß-HMGB1 signaling pathway.

Vascular smooth muscle cells (VSMCs) under biophysical stress play an active role in the progression of vascular inflammation, but the precise mechanisms are unclear. This study examined the cellular expression of monocyte chemoattractant protein 1 (MCP-1) and its related mechanisms using cultured rat aortic VSMCs stimulated with mechanical stretch (MS, equibiaxial cyclic stretch, 60 cycles/ min). When the cells were stimulated with 10% MS, MCP-1 expression was markedly increased compared to those in the cells stimulated with low MS intensity (3% or 5%). An enzyme-linked immunosorbent assay revealed an increase in HMGB1 released into culture media from the cells stimulated with 10% MS compared to those stimulated with 3% MS. A pretreatment with glycyrrhizin, a HMGB1 inhibitor, resulted in the marked attenuation of MCP-1 expression in the cells stimulated with 10% MS, suggesting a key role of HMGB1 on MCP-1 expression. Western blot analysis revealed higher PDGFR-α and PDGFR-ß expression in the cells stimulated with 10% MS than 3% MS-stimulated cells. In the cells deficient of PDGFR-ß using siRNA, but not PDGFR-α, HMGB1 released into culture media was significantly attenuated in the 10% MS-stimulated cells. Similarly, MCP-1 expression induced in 10% MS-stimulated cells was also attenuated in cells deficient of PDGFR-ß. Overall, the PDGFR-ß signaling plays a pivotal role in the increased expression of MCP-1 in VSMCs stressed with 10% MS. Therefore, targeting PDGFR-ß signaling in VSMCs might be a promising therapeutic strategy for vascular complications in the vasculatures under excessive biophysical stress.

Association of TP53 Mutation Status and Sex with Clinical Outcome in NSCLC Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

Purpose: Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC. Materials and Methods: Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed. Results: In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT. Conclusion: Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Proximally positioned femoral grafts decrease passive anterior tibial subluxation in anterior cruciate ligament reconstruction using a posterior trans-septal portal.

PURPOSE: To compare the anterior and posterior trans-septal (TS) portal approaches in anterior cruciate ligament reconstruction (ACLR) by evaluating femoral tunnel positioning and passive anterior tibial subluxation (PATS). METHODS: A total of 205 patients who underwent primary ACLR using the outside-in technique between March 2018 and December 2021 were retrospectively enrolled. Patients were classified into two groups based on the viewing techniques: the anterior group was treated using anteromedial or anterolateral portals (n = 155), and the TS group was treated using posterior TS portal (n = 55). The relative locations of the femoral tunnel were evaluated using the deep-shallow planes (X-axis) and superior-inferior planes (Y-axis) with the quadrant method in the lateral femoral condyle on a 3-dimensional computed tomography image. Anterior tibial subluxation for the lateral and medial compartments relative to the femoral condyles was evaluated as measured on magnetic resonance imaging. Knee laxity was assessed using the pivot-shift test and stress radiography. RESULTS: In the posterior TS group, the femoral tunnel was usually located deeper on the X-axis and more superior on the Y-axis, which corresponds to a more proximal position, than in the anterior group (deeper on the X-axis and superior on the Y-axis). Moreover, the femoral tunnel locations in this group were more compactly distributed than those in the anterior group. The TS group showed significantly better reduction of postoperative PATS in the lateral compartments than the anterior group (anterior group vs. TS group: lateral compartment, 3.2 ± 3.1 vs. 4.5 ± 3.2 mm; p = .016). Significantly better results were found in the TS group for knee stability as assessed by the pivot-shift grade (p = .044); however, there were no significant differences between the two groups with respect to patient-reported outcome measures (p > .05) and other complications (p = .090). CONCLUSION: Our results suggest that positioning the femoral tunnel using the posterior TS portal approach may lead to better outcomes in terms of PATS and rotational stability compared to the anterior portal approach in ACLR.

Anti-Inflammatory Effect of Atorvastatin and Rosuvastatin on Monosodium Urate-Induced Inflammation through IL-37/Smad3-Complex Activation in an In Vitro Study Using THP-1 Macrophages.

Objective: The pleiotropic effect of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is responsible for potent defense against inflammatory response. This study evaluated the inhibitory effects of HMG-CoA reductase inhibitors on the monosodium urate (MSU)-induced inflammatory response through the regulation of interleukin-37 (IL-37) expression. Methods: Serum was collected from patients with gout (n = 40) and from healthy controls (n = 30). The mRNA and protein expression of the target molecules IL-1ß, IL-37, caspase-1, and Smad3 were measured in THP-1 macrophages stimulated with MSU, atorvastatin, or rosuvastatin using a real-time quantitative polymerase chain reaction and Western blot assay. Transfection with IL-1ß or Smad3 siRNA in THP-1 macrophages was used to verify the pharmaceutical effect of statins in uric-acid-induced inflammation. Results: Serum IL-37 levels in gout patients were significantly higher than in controls (p < 0.001) and was associated with the serum uric acid level (r = 0.382, p = 0.008). THP-1 cells stimulated with MSU markedly induced IL-37 mRNA expression and the transition of IL-37 from the cytoplasm to the nucleus. Recombinant IL-37 treatment dose-dependently inhibited activation of caspase-1 and IL-1ß in MSU-induced inflammation. Atorvastatin and rosuvastatin attenuated caspase-1 activation and mature IL-1ß expression but augmented translocation of IL-37 from the cytoplasm to the nucleus. Atorvastatin and rosuvastatin induced phosphorylation of Smad3 in THP-1 cells treated with MSU crystals. Statins potently attenuated translocation of IL-37 from the cytoplasm to the nucleus in THP-1 macrophages transfected with Smad3 siRNA compared to cells with negative control siRNA. Conclusions: This study revealed that statins inhibit the MSU-induced inflammatory response through phosphorylated Smad3-mediated IL-37 expression in THP-1 macrophages.

Randomized, Double-Blind, Active-Controlled Phase 3 Study to Evaluate Efficacy and Safety of Zastaprazan Compared With Esomeprazole in Erosive Esophagitis.

INTRODUCTION: Zastaprazan is a potent potassium-competitive acid blocker developed to treat gastroesophageal reflux disease. The aim of this study was to evaluate the efficacy and safety of zastaprazan compared with esomeprazole in patient with erosive esophagitis (EE). METHODS: A phase III, multicenter, randomized, double-blind, noninferiority clinical study was conducted with 300 subjects with confirmed EE. Subjects were randomized to receive zastaprazan 20 mg or esomeprazole 40 mg once daily up to 8 weeks. The primary end point was the cumulative proportion of subject with healed EE confirmed by endoscopy at week 8. The secondary end points included the healing rate at week 4, symptom response, and quality of life assessment. Safety profiles and serum gastrin levels were also assessed. RESULTS: In the full analysis set, the cumulative healing rate at week 8 were 97.92% (141/144) for zastaprazan and 94.93% (131/138) ( P = 0.178) for esomeprazole. The healing rate at week 4 in the zastaprazan group was higher than the esomeprazole group (95.14% [137/144] vs 87.68% [121/138]; P = 0.026). There was no significant difference between groups in healing rates (the per-protocol set) at week 8 and week 4, symptom responses, quality of life assessments, and safety profiles. In addition, serum gastrin levels increased during treatment in both groups, with a significant difference between the 2 groups ( P = 0.047), but both decreased after treatment. DISCUSSION: An 8-week therapy of zastaprazan 20 mg is noninferior to esomeprazole 40 mg in subjects with predominantly low-grade EE. The healing rate at week 4 appears to be higher for zastaprazan than esomeprazole.

Updates on the mechanisms of toxicities associated with monoclonal antibodies targeting growth factor signaling and immune cells in cancer.

Monoclonal antibody (mAb)-based immunotherapy currently is considered to be an optimal therapeutic approach to cancer treatment, either in combination with surgery, radiation, and/or chemotherapy or alone. Various solid tumors and hematological malignancies have been characterized by distinct molecular targets, which could be utilized as innovative anticancer agents. Notably, receptor tyrosine kinases, including HER2, EGFR, VEGFR, and PDGFR, which act as receptors for growth factors, serve as crucial target proteins, expanding their role in the cancer therapeutic market. In contrast to conventional anticancer agents that directly target cancer cells, the advent of immunotherapy introduces novel approaches, such as immune checkpoint blockers (ICBs) and mAbs targeting surface antigens on immune cells in hematological malignancies and lymphomas. While these immunotherapies have mitigated the acquired resistance observed in traditional targeted therapies, they also exhibit diverse toxicities. Herein, this review focuses on describing the well-established toxicities and newly proposed mechanisms of monoclonal antibody toxicity in recent studies. Understanding these molecular mechanisms is indispensable to overcoming the limitations of mAbs-based therapies, facilitating the development of innovative anticancer agents, and uncovering novel indications for cancer treatment in the future.