Prolonged progression-free survival achieved by gemcitabine, cisplatin, and albumin-bound paclitaxel for the treatment of advanced biliary tract cancers.

Background: A regimen of gemcitabine, cisplatin, and nab-paclitaxel (GPA) has shown promising results in patients with advanced biliary tract cancer (aBTC). Objectives: This study aimed to evaluate the benefit of GPA compared to a regimen of gemcitabine plus cisplatin (GP) in patients with aBTC. Design: Retrospective study. Methods: Patients with aBTC who received first-line chemotherapy with GPA or GP regimen at the Samsung Medical Center between July 2020 and June 2022 were included. The primary endpoint was progression-free survival (PFS). Results: In all, 37 patients were treated with GPA and 43 patients with GP. The GPA group showed significantly longer median PFS [12.0 months (95% CI, 7.2-16.8)] compared to the GP group [5.5 months (95% CI, 3.7-7.4; p = 0.007)]. The median overall survival (OS) was also longer in the GPA group [18.7 months (95% CI, 13.7-23.7)] than in the GP group [10.7 months (95% CI, 1.5-19.9); p = 0.021]. First-line chemotherapy with GPA was associated with longer PFS, while metastatic disease at initial diagnosis and post-treatment increase in CA 19-9 level were associated with worse PFS. Conclusion: The GPA regimen improved the PFS of patients with aBTC compared to the GP regimen but showed no significant benefit in terms of OS after adjusting for confounding variables. Further large-scale studies are required to establish optimal indications for GPA.

Comparing new and standard chemotherapy treatments for advanced biliary tract cancer: a study of effectiveness and survival In this study, researchers at Samsung Medical Center investigated the effectiveness of two chemotherapy regimens for advanced biliary tract cancer (aBTC) from July 2020 to June 2022. The study compared a new treatment combination, gemcitabine, cisplatin, and nab-paclitaxel (GPA), against the standard treatment of gemcitabine and cisplatin (GP). The main focus was on progression-free survival (PFS) ­ the time patients lived without their cancer worsening, and overall survival (OS) ­ the total lifespan after treatment. A total of 37 patients received the GPA treatment, while 43 received the GP treatment. The results showed that patients on the GPA regimen had a longer median PFS of 12.0 months, compared to 5.5 months for those on the GP regimen. This significant difference suggested that GPA might be more effective in slowing cancer progression. Moreover, the median OS was also longer for patients treated with GPA (18.7 months) than for those with the GP regimen (10.7 months). These findings indicated that GPA not only delayed the progression of cancer but also potentially increased the overall survival time of patients. However, when accounting for other factors that could influence the results, the advantage of GPA in terms of overall survival became less clear. This suggests that while GPA is effective in delaying disease progression, its impact on extending the overall life expectancy of patients with aBTC is not definitive. Despite these promising findings, the researchers cautioned that the benefits of the GPA regimen in extending overall survival need further investigation. The study underscores the potential of GPA in improving outcomes for aBTC patients but also highlights the necessity for more comprehensive studies. These future studies are needed to confirm the optimal treatment for this challenging cancer type. This research is a step towards better understanding and managing aBTC, a cancer that currently has limited treatment options.

Susceptibility to Fosfomycin and Nitrofurantoin of ESBL-Positive Escherichia coli and Klebsiella pneumoniae Isolated From Urine of Pediatric Patients.

BACKGROUND: Pediatric urinary tract infection (UTI) caused by extended-spectrum ß-lactamase (ESBL)-positive gram-negative bacilli (GNB) has limited options for oral antibiotic treatment. The purpose of this study was to investigate the susceptibility of ESBL-positive Escherichia coli and Klebsiella pneumoniae isolates from pediatric urine samples to two oral antibiotics (fosfomycin and nitrofurantoin). METHODS: From November 2020 to April 2022, ESBL-positive E. coli and K. pneumoniae isolates from urine samples were collected at Samsung Medical Center, Seoul, Korea. Patients over 18 years of age or with malignancy were excluded. For repeated isolates from the same patient, only the first isolate was tested. Minimum inhibitory concentrations (MICs) were measured using agar (fosfomycin) or broth (nitrofurantoin) dilution methods. MIC50 and MIC90 were measured for fosfomycin and nitrofurantoin in both E. coli and K. pneumoniae. RESULTS: There were 117 isolates from 117 patients, with a median age of 7 months (range, 0.0-18.5 years). Among 117 isolates, 92.3% (108/117) were E. coli and 7.7% (9/117) were K. pneumoniae. Isolates from the pediatric intensive care unit (PICU) and general ward (GW) was 11.1% (13/117) and 88.9% (104/117), respectively. Among 108 E. coli isolates, MIC50 and MIC90 for fosfomycin were 0.5 µg/mL and 2 µg/mL, respectively. Fosfomycin susceptibility rate was 97.2% (105/108) with a breakpoint of 128 µg/mL. Fosfomycin susceptibility rate was significantly lower in PICU isolates than in GW isolates (81.8% vs. 99.0%, P = 0.027). For nitrofurantoin, both the MIC50 and MIC90 were 16 µg/mL. Nitrofurantoin susceptibility rate was 96.3% (104/108) with a breakpoint of 64 µg/mL based on Clinical and Laboratory Standards Institute guidelines. Among the nine K. pneumoniae isolates, the MIC50 and MIC90 for fosfomycin was 2 µg/mL and 32 µg/mL, respectively. MIC50 and MIC90 for nitrofurantoin were 64 µg/mL and 128 µg/mL, respectively. CONCLUSION: For uncomplicated UTI caused by ESBL-positive GNB in Korean children, treatment with fosfomycin and nitrofurantoin for E. coli infections can be considered as an effective oral therapy option.

LC-MS/MS-based serum proteomics reveals a distinctive signature in a rheumatoid arthritis mouse model after treatment with mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are known to be able to modulate immune responses, possess tissue-protective properties, and exhibit healing capacities with therapeutic potential for various diseases. The ability of MSCs to secrete various cytokines and growth factors provides new insights into autoimmune-diseases such as rheumatoid arthritis (RA). RA is a systemic autoimmune disease that affects the lining of synovial joints, causing stiffness, pain, inflammation, and joint erosion. In recent years, MSCs-based therapies have been widely proposed as promising therapies in the treatment of RA. However, the mechanism involved in disease-specific therapeutic effects of MSCs on RA remains unclear. To clarify the mechanism involved in effects of MSCs on RA, proteomic profiling was performed using an RA mouse model before and after treatment with MSCs. In this study, treatment efficacy of human umbilical cord blood-mesenchymal stem cells (hUCB-MSCs) was confirmed using a type II collagen-induced arthritis (CIA) mouse model. Results of measuring incidence rates of arthritis and clinical arthritis index (CAI) revealed that mice administrated with hUCB-MSCs had a significant reduction in arthritis severity. Proteins that might affect disease progression and therapeutic efficacy of hUCB-MSC were identified through LC-MS/MS analysis using serum samples. In addition, L-1000 analysis was performed for hUCB-MSC culture medium. To analysis data obtained from LC-MS/MS and L-1000, tools such as ExDEGA, MEV, and DAVID GO were used. Results showed that various factors secreted from hUCB-MSCs might play roles in therapeutic effects of MSCs on RA, with platelet activation possibly playing a pivotal role. Results of this study also suggest that SERPINE1 and THBS1 among substances secreted by hUCB-MSC might be key factors that can inhibit platelet activation. This paper is expected to improve our understanding of mechanisms involved in treatment effects of stem cells on rheumatoid arthritis.

Immunomodulatory Effect of Epidermal Growth Factor Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells on Atopic Dermatitis.

Background and Objectives: Human mesenchymal stem cells (MSCs) are emerging as a treatment for atopic dermatitis (AD), a chronic inflammatory skin disorder that affects a large number of people across the world. Treatment of AD using human umbilical cord blood-derived MSCs (hUCB-MSCs) has recently been studied. However, the mechanism underlying their effect needs to be studied continuously. Thus, the objective of this study was to investigate the immunomodulatory effect of epidermal growth factor (EGF) secreted by hUCB-MSCs on AD. Methods and Results: To explore the mechanism involved in the therapeutic effect of MSCs for AD, a secretome array was performed using culture medium of hUCB-MSCs. Among the list of genes common for epithelium development and skin diseases, we focused on the function of EGF. To elucidate the effect of EGF secreted by hUCB-MSCs, EGF was downregulated in hUCB-MSCs using EGF-targeting small interfering RNA. These cells were then co-cultured with keratinocytes, Th2 cells, and mast cells. Depletion of EGF disrupted immunomodulatory effects of hUCB-MSCs on these AD-related inflammatory cells. In a Dermatophagoides farinae-induced AD mouse model, subcutaneous injection of hUCB-MSCs ameliorated gross scoring, histopathologic damage, and mast cell infiltration. It also significantly reduced levels of inflammatory cytokines including interleukin (IL)-4, tumor necrosis factor (TNF)-α, thymus and activation-regulated chemokine (TARC), and IL-22, as well as IgE levels. These therapeutic effects were significantly attenuated at all evaluation points in mice injected with EGF-depleted hUCB-MSCs. Conclusions: EGF secreted by hUCB-MSCs can improve AD by regulating inflammatory responses of keratinocytes, Th2 cells, and mast cells.

Translation and validation of the Korean Version of the Reflux Symptom Score.

OBJECTIVES: To assess the validity and reliability of the Korean version of the reflux symptom score (K-RSS). MATERIALS AND METHODS: The English version of the RSS was translated into Korean and completed by 77 people (44 and 33 people in the patient group and control group, respectively). They completed the K-RSS (K-RSS-1) and reflux symptom index (RSI) questionnaires and answered questions about age, sex, underlying disease, smoking history, and alcohol and coffee consumption. They completed the K-RSS once more (K-RSS-2) after 1 - 2 weeks. Internal consistency was evaluated using Cronbach's α and test-retest reliability using the intraclass correlation coefficient (ICC). External validity was evaluated using the Spearman rank test between the RSI and K-RSS. The Mann-Whitney U test was used to assess internal validity by comparing the K-RSS-1 scores between the patient and control groups. RESULTS: The most common symptoms were globus sensation, throat clearing, and throat pain. The K-RSS reported high internal consistency (α = 0.894). The ICC for the total score was 0.883, indicating excellent test-retest reliability. According to the Spearman analysis, there was a significant correlation between the total score of the K-RSS and that of the RSI (rs = 0.902; P < 0.001), demonstrating strong external validity. Furthermore, the patient group showed significantly higher values than the control group in all K-RSS scores, suggesting high internal validity. CONCLUSION: The K-RSS is a patient-reported outcome questionnaire with excellent criterion-referenced validity and ideal reliability.

Pimecrolimus interferes the therapeutic efficacy of human mesenchymal stem cells in atopic dermatitis by regulating NFAT-COX2 signaling.

BACKGROUND: Human mesenchymal stem cells (hMSCs) therapy has recently been considered a promising treatment for atopic dermatitis (AD) due to their immunomodulation and tissue regeneration ability. In our previous studies, we demonstrated that hMSCs alleviate allergic inflammation in murine AD model by inhibiting the activation of mast cells and B cells. Also our phase I/IIa clinical trial showed clinical efficacy and safety of hMSCs in moderate-to-severe adult AD patients. However, hMSCs therapy against atopic dermatitis have had poor results in clinical field. Therefore, we investigated the reason behind this result. We hypothesized that drug-cell interaction could interfere with the therapeutic efficacy of stem cells, and investigated whether coadministration with pimecrolimus, one of the topical calcineurin inhibitors, could influence the therapeutic potential of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) in AD. METHODS: hUCB-MSCs were subcutaneously injected to AD-induced mice with or without pimecrolimus topical application. To examine whether pimecrolimus influenced the immunomodulatory activity of hUCB-MSCs, hUCB-MSCs were treated with pimecrolimus. RESULTS: Pimecrolimus disturbed the therapeutic effect of hUCB-MSCs when they were co-administered in murine AD model. Moreover, the inhibitory functions of hUCB-MSCs against type 2 helper T (Th2) cell differentiation and mast cell activation were also deteriorated by pimecrolimus treatment. Interestingly, we found that pimecrolimus decreased the production of PGE2, one of the most critical immunomodulatory factors in hUCB-MSCs. And we demonstrated that pimecrolimus downregulated COX2-PGE2 axis by inhibiting nuclear translocation of NFAT3. CONCLUSIONS: Coadministration of pimecrolimus with hMSCs could interfere with the therapeutic efficacy of hMSCs in atopic dermatitis, and this is the first study that figured out the interaction of hMSCs with other drugs in cell therapy of atopic dermatitis. Therefore, this study might give rise to improvement of the clinical application of hMSCs therapy and facilitate the widespread application of hMSCs in clinical field.