Background:
Tofacitinib is a small molecule that inhibits Janus kinase and has been reported to be effective in Western patients with ulcerative colitis (UC). However, the real-life data on ...tofacitinib in Asian UC patients are limited.
Objective:
To investigate the real-life effectiveness and safety of tofacitinib induction and maintenance treatment in Korean patients with UC.
Design:
This was a retrospective study on patients with UC who received tofacitinib treatment at 12 hospitals in Korea between January 2018 and November 2020.
Methods:
Clinical remission at week 52, defined as a partial Mayo score of ⩽2 with a combined rectal bleeding subscore and stool frequency subscore of ⩽1, was used as the primary outcome. Adverse events (AEs), including herpes zoster and deep vein thrombosis, were also evaluated.
Results:
A total of 148 patients with UC were started on tofacitinib. Clinical remission rates of 60.6%, 54.9%, and 52.8% were reported at weeks 16, 24, and 52, respectively. Clinical response rates of 71.8%, 67.6%, and 59.9% were reported at weeks 16, 24, and 52, respectively. Endoscopic remission rates at weeks 16 and 52 were 52.4% and 30.8% based on the Mayo endoscopic subscore and 20.7% and 15.2% based on the UC endoscopic index of severity (UCEIS), respectively. A higher UCEIS at baseline was negatively associated with clinical response adjusted odds ratio (aOR): 0.774, p = 0.029 and corticosteroid-free clinical response (aOR: 0.782, p = 0.035) at week 52. AEs occurred in 19 patients (12.8%) and serious AEs in 12 patients (8.1%). Herpes zoster occurred in four patients (2.7%). One patient (0.7%) suffered from deep vein thrombosis.
Conclusions:
Tofacitinib was an effective induction and maintenance treatment with an acceptable safety profile in Korean patients with UC.
Plain language summary
Real-life effectiveness and safety of tofacitinib treatment in Korean patients with ulcerative colitis
Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colonic mucosa that usually presents with bloody diarrhea and abdominal pain. Tofacitinib is a small molecule that inhibits Janus kinase and has been reported to be effective in Western patients with UC. However, real-life data on the effectiveness of tofacitinib in Asian patients with UC are limited. To investigate the real-life effectiveness and safety of tofacitinib treatment in Korean patients with UC, we retrospectively analyzed the data of 148 patients with UC who received tofacitinib treatment at 12 hospitals in Korea between January 2018 and November 2020. Clinical remission (i.e. complete improvement of symptoms) was achieved in 60.6% and 52.8% of patients at weeks 16 and 52, respectively. Endoscopic remission was achieved in 52.4% and 30.8% of patients at weeks 16 and 52, respectively. A higher baseline score of the UC endoscopic index of severity, which is one of the endoscopic indices that evaluate the severity of inflammation of the colon, was negatively associated with clinical response (i.e. partial improvement of symptoms). Adverse events (AEs) including herpes zoster and deep vein thrombosis occurred in 19 patients (12.8%) and serious AEs occurred in 12 patients (8.1%). Our real-life study shows that tofacitinib is a clinically effective treatment for Korean patients with UC, and the incidence of AEs was also similar to those observed in other real-world studies.
Abstract
Background
Endoscopic submucosal dissection (ESD) can provide a high en bloc resection rate and has been widely applied as curative treatment for early colorectal cancer (ECC). However, ...surgical treatment is occasionally required, and reports on the long-term prognosis of ESD are insufficient. This study aimed to investigate the long-term outcomes of ECC removal by ESD, including local recurrence and metastasis.
Methods
This multicenter study was conducted retrospectively on 450 consecutive patients with ECC who were treated with ESD between November 2003 and December 2013. Clinical, pathological, and endoscopic data were collected to determine tumor depth, resection margin, lymphovascular invasion, and recurrence.
Results
The median follow-up period was 53.8 (12–138 months). The en bloc resection rate was 85.3% (384) and in intramucosal cancer being 84.1% and in superficial submucosal invasion (SM1) cancer being 89.8% (
p
= 0.158). The curative resection rate was 76.0% (n = 342), and there was no statistical difference between the two groups (77.3% vs. 71.4%,
p
= 0.231). The overall recurrence free survival rate (RFS) was 98.7% (444/450). In patients with curative resection, there was no statistically significant difference in RFS according to invasion depth (intramucosal: 99.3% vs. SM1: 97.1%,
p
= 0.248).
Conclusions
Patients with curatively resected ECC treated with ESD showed favorable long-term outcomes. Curatively resected SM1 cancer has a RFS similar to that of intramucosal cancer.
Lysosomes are closely linked to autophagic activity, which plays a vital role in pancreatic ductal adenocarcinoma (PDAC) biology. The survival of PDAC patients is still poor, and the identification ...of novel genetic factors for prognosis and treatment is highly required to prevent PDAC-related deaths. This study investigated the germline variants related to lysosomal dysfunction in patients with PDAC and to analyze whether they contribute to the development of PDAC.
The germline putative pathogenic variants (PPV) in genes involved in lysosomal storage disease (LSD) was compared between patients with PDAC (n = 418) and healthy controls (n = 845) using targeted panel and whole-exome sequencing. Furthermore, pancreatic organoids from wild-type and Kras
mice were used to evaluate the effect of lysosomal dysfunction on PDAC development. RNA sequencing (RNA-seq) analysis was performed with established PDAC patient-derived organoids (PDOs) according to the PPV status.
The PPV in LSD-related genes was higher in patients with PDAC than in healthy controls (8.13 vs. 4.26%, Log
OR = 1.65, P = 3.08 × 10
). The PPV carriers of LSD-related genes with PDAC were significantly younger than the non-carriers (mean age 61.5 vs. 65.3 years, P = 0.031). We further studied a variant of the lysosomal enzyme, galactosylceramidase (GALC), which was the most frequently detected LSD variant in our cohort. Autophagolysosomal activity was hampered when GALC was downregulated, which was accompanied by paradoxically elevated autophagic flux. Furthermore, the number of proliferating Ki-67
cells increased significantly in pancreatic organoids derived from Galc knockout Kras
mice. Moreover, GALC PPV carriers tended to show drug resistance in both PDAC cell line and PDAC PDO, and RNA-seq analysis revealed that various metabolism and gene repair pathways were upregulated in PDAC PDOs harboring a GALC variant.
Genetically defined lysosomal dysfunction is frequently observed in patients with young-onset PDAC. This might contribute to PDAC development by altering metabolism and impairing autophagolysosomal activity, which could be potentially implicated in therapeutic applications for PDAC.
The main objective of this study was to prepare a solid form of lipid-based self-emulsifying drug delivery system (SEDDS) by spray drying liquid SEDDS with an inert solid carrier Aerosil 200 to ...improve the oral bioavailability of poorly water-soluble drug dexibuprofen. The liquid SEDDS was a system that consisted of dexibuprofen, Labrasol, Capryol 90 and Labrafil M 1944 CS. The particle size analysis revealed no difference in the
z-average particle diameter of the reconstituted emulsion between liquid and solid SEDDS. The solid SEDDS was characterized by SEM, DSC and XRD studies. In vivo results of solid SEDDS and dexibuprofen powder in rats at the dose of 10
mg/kg showed that the initial plasma concentrations of drug in solid SEDDS were significantly higher than those of dexibuprofen powder (
P
<
0.05). The solid SEDDS gave significantly higher AUC and Cmax than did dexibuprofen powder (
P
<
0.05). In particular, the AUC of solid SEDDS was about twofold higher than that of dexibuprofen powder. Our results suggested that this solid SEDDS could be used as an effective oral solid dosage form to improve the bioavailability of poorly water-soluble drug dexibuprofen.
Despite its wide use as a first-line therapeutic agent, gemcitabine has shown limited efficacy in advanced pancreatic cancer due to chemoresistance by as yet unidentified mechanisms. Our goal here ...was to identify molecular features involved in gemcitabine chemoresistance. Pyruvate kinase M2 (PKM2), a key enzyme of aerobic glycolysis, has recently emerged as an important therapeutic target for cancer treatment. It is involved in the metabolic reprogramming of cancer cells and has previously unexpected non-metabolic functions that are heavily involved in tumor growth and survival. Herein, we report that the chemoresistance of pancreatic cancer to gemcitabine was dependent on PKM2 expression and its non-metabolic function. Knocking-down of PKM2 significantly enhanced gemcitabine-induced cell apoptosis through the activation of caspase 3/7 and PARP cleavage, and this inhibitory activity was associated with p38-mediated activation of p53 phosphorylation at serine 46. Our findings support the potential of PKM2 as a novel target for gemcitabine chemoresistance and suggest the feasibility of combining gemcitabine and PKM2 inhibition for the improved chemotherapy of pancreatic cancer.
•PKM2 knock-down augments gemcitabine-induced apoptosis in pancreatic cancer cells.•PKM2 blocks gemcitabine-induced activation of p53 by inhibiting p38 activity.•Non-metabolic PKM2 inhibits gemcitabine cytotoxicity.•PKM2 is a potential target in gemcitabine-resistant pancreatic cancer cells.
Despite the significant reduction decades ago in sudden unexpected death in infancy (SUDI), decline of rates has slowed and stalled in some countries, including the USA. This led to an appreciation ...of ethnic variations in SUDI rates and the need to increase cultural sensitivity regarding sleep practices and circumstantial factors of SUDI. The study explored SUDI-related factors, in journal articles from two geo-cultural regions (Asian and Western countries), particularly for factors related to infant sleep practices.
A systematic review was conducted to identify SUDI-related factors in articles from PubMed, Scopus, and the Korean Citation Index from January 1992 to April 2019. From each article, SUDI-related factors were retrieved and categorized through the identification, aggregation, and categorization of factors into the areas of the triple risk model (TRM) of SUDI by their meanings and commonality. Significant trends in the frequency of factors were analyzed across time and between the two geo-cultural regions (Asian and Western countries) of article.
From a review of 218 articles (38 Asian and 180 Western articles), 84 SUDI-related factors were identified: 39 factors for TRM 1, 44 factors for TRM 2, and one factor for TRM 3. Four of the top-ranked 10 factors were found in both cultural zones: sleep position, male sex, bed-sharing, and genetics. Both cultural zones identified sleep position (44.0%), bed-sharing (22.0%), and rooming-in (16.5%) as the three most important sleep-related factors for SUDI. Variations between the cultural zones were observed in the place of SUDI occurrence, overheating, swaddling or bedding standards, and smoking.
Regardless of the urgent need to identify SUDI-related factors in low-SUDI societies, Asian cultures showed a significant lack of articles on SUDI. Several sociocultural issues were recognized such as the meaning of bed-sharing and rooming-in, along with residential styles and traditional health beliefs on sleep-related SUDI factors. Particularly little attention towards smoking was found in Asian articles in terms of frequency, suggesting the need to enhance SUDI reduction strategies by incorporating gender-sensitive smoking cessation interventions. This review of SUDI factors requests child health professionals to be alert to sociocultural variations in sleep practices and SUDI factors.
Crohn's disease (CD) is an intractable inflammatory bowel disease of unknown cause. Recent genome-wide association studies of CD in Korean and Japanese populations suggested marginal sharing of ...susceptibility loci between Caucasian and Asian populations. As the 7 identified loci altogether explain 5.31% of the risk for CD, the objective of this study was to identify additional CD susceptibility loci in the Korean population.
Using the ImmunoChip custom single-nucleotide polymorphism array designed for dense genotyping of 186 loci identified through GWAS, we analyzed 722 individuals with CD and 461 controls for 96,048 SNP markers in the discovery stage, followed by validation in an additional 948 affected individuals and 977 controls.
We confirmed 6 previously reported loci in Caucasian: GPR35 at 2q37 (rs3749172; P = 5.30 × 10, odds ratio OR = 1.45), ZNF365 at 10q21 (rs224143; P = 2.20 × 10, OR = 1.38), ZMIZ1 at 10q22 (rs1250569; P = 3.05 × 10, OR = 1.30), NKX2-3 at 10q24 (rs4409764; P = 7.93 × 10, OR = 1.32), PTPN2 at 18p11 (rs514000; P = 9.00 × 10, OR = 1.33), and USP25 at 21q11 (rs2823256; P = 2.49 × 10, OR = 1.35), bringing the number of known CD loci (including 3 in the HLA) in Koreans to 15. The 6 additional loci increased the total genetic variance for CD risk from 5.31% to 7.27% in Koreans.
Although the different genetic backgrounds of CD between Asian and Western countries has been well established for the major susceptibility genes, our findings of overlapping associations offer new insights into the genetic architecture of CD.
The prospective Crohn's Disease Clinical Network and Cohort study is a nationwide multicenter cohort study of patients with Crohn's disease (CD) in Korea, aiming to prospectively investigate the ...clinical features and long-term prognosis associated with CD.
Patients diagnosed with CD between January 2009 and September 2019 were prospectively enrolled. They were divided into two cohorts according to the year of diagnosis: cohort 1 (diagnosed between 2009 and 2011) versus cohort 2 (between 2012 and 2019).
A total of 1,175 patients were included, and the median follow-up duration was 68 months (interquartile range, 39.0 to 91.0 months). The treatment-free durations for thiopurines (p<0.001) and anti-tumor necrosis factor agents (p=0.018) of cohort 2 were shorter than those of cohort 1. Among 887 patients with B1 behavior at diagnosis, 149 patients (16.8%) progressed to either B2 or B3 behavior during follow-up. Early use of thiopurine was associated with a reduced risk of behavioral progression (adjusted hazard ratio aHR, 0.69; 95% confidence interval CI, 0.50 to 0.90), and family history of inflammatory bowel disease was associated with an increased risk of behavioral progression (aHR, 2.29; 95% CI, 1.16 to 4.50). One hundred forty-one patients (12.0%) underwent intestinal resection, and the intestinal resection-free survival time was significantly longer in cohort 2 than in cohort 1 (p=0.003). The early use of thiopurines (aHR, 0.35; 95% CI, 0.23 to 0.51) was independently associated with a reduced risk of intestinal resection.
The prognosis of CD in Korea appears to have improved over time, as evidenced by the decreasing intestinal resection rate. Early use of thiopurines was associated with an improved prognosis represented by a reduced risk of intestinal resection.
Many studies have demonstrated the mechanisms of progression to castration-resistant prostate cancer (CRPC) and novel strategies for its treatment. Despite these advances, the molecular mechanisms ...underlying the progression to CRPC remain unclear, and currently, no effective treatments for CRPC are available. Here, we characterized the key genes involved in CRPC progression to gain insight into potential therapeutic targets. Bicalutamide-resistant prostate cancer cells derived from LNCaP were generated and named Bical R. RNA sequencing was used to identify differentially expressed genes (DEGs) between LNCaP and Bical R. In total, 631 DEGs (302 upregulated genes and 329 downregulated genes) were identified. The Cytohubba plug-in in Cytoscape was used to identify seven hub genes (
,
,
,
,
,
, and
) associated with CRPC progression. Among these hub genes,
and
were markedly upregulated in CRPC cell lines and CRPC patient samples. The patients with high expression of
and
showed worse disease-free survival in patients with The Cancer Genome Atlas (TCGA)-prostate adenocarcinoma (PRAD) datasets. Our study revealed a potential association between
and
and the progression to CRPC. These results may contribute to the development of potential therapeutic targets and mechanisms underlying CRPC progression, aiming to improve clinical efficacy in CRPC treatment.
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