Search

ABSTRACT Background/Aims The differences in the clinical course of Crohn's disease (CD) and ulcerative colitis (UC) among Asian countries remain unknown. Thus, we compared the clinical characteristics, treatment, and one‐year outcomes of newly diagnosed inflammatory bowel disease (IBD) patients between Vietnam and Korea. Methods A retrospective cohort study was conducted at seven tertiary hospitals in these countries between January 2020 and January 2021. Data on demographics, diseases, treatment, and outcomes during 1 year after diagnosis were collected. Results Among 225 patients (60 from Vietnam and 165 from Korea), 140 and 85 were diagnosed with UC and CD, respectively. Severe activity (p 0.05). Conclusions Although Vietnamese IBD patients had higher baseline clinical and phenotypic severity than their Korean counterparts, no significant differences in short‐term outcomes were observed, potentially reflecting the impact of the higher rate and early biologic usage in Vietnamese patients.

ABSTRACT Background The prognostic significance of extranodal sites in stage IV diffuse large B‐cell lymphoma (DLBCL) remains uncertain, making it challenging to select appropriate treatment strategies for individual patients. In this study, we aimed to evaluate the influence of different extranodal sites on prognosis in young patients with stage IV DLBCL who achieved complete remission (CR) following initial chemo‐immunotherapy and to explore the potential of autologous hematopoietic stem cell transplantation (ASCT) as a consolidation treatment for specific patient subgroups. Methods We retrospectively reviewed data from 119 patients with DLBCL aged

Abstract Autophagy is a crucial quality control mechanism that degrades damaged cellular components through lysosomal fusion with autophagosomes. However, elevated autophagy levels can promote drug resistance in cancer cells, enhancing their survival. Downregulation of autophagy through oxidative stress is a clinically promising strategy to counteract drug resistance, yet precise control of oxidative stress in autophagic proteins remains challenging. Here, a molecular design strategy of biocompatible neutral Ir(III) photosensitizers is demonstrated, B2 and B4, for precise reactive oxygen species (ROS) control at lysosomes to inhibit autophagy. The underlying molecular mechanisms for the biocompatibility and lysosome selectivity of Ir(III) complexes are explored by comparing B2 with the cationic or the non‐lysosome‐targeting analogs. Also, the biological mechanisms for autophagy inhibition via lysosomal oxidation are explored. Proteome analyses reveal significant oxidation of proteins essential for autophagy, including lysosomal and fusion‐mediator proteins. These findings are verified in vitro, using mass spectrometry, live cell imaging, and a model SNARE complex. The anti‐tumor efficacy of the precise lysosomal oxidation strategy is further validated in vivo with B4, engineered for red light absorbance. This study is expected to inspire the therapeutic use of spatiotemporal ROS control for sophisticated modulation of autophagy.

During cervical carcinogenesis, T‐helper (Th)‐17 cells accumulate in the peripheral blood and tumor tissues of cancer patients. We previously demonstrated that Th17 cells are associated with therapy resistance as well as cervical cancer metastases and relapse; however, the underlying Th17‐driven mechanisms are not fully understood. Here, using microarrays, we found that Th17 cells induced an epithelial‐to‐mesenchymal transition (EMT) phenotype of cervical cancer cells and promoted migration and invasion of 2D cultures and 3D spheroids via induction of microRNA miR‐142‐5p. As the responsible mechanism, we identified the subunits C and D of the succinate dehydrogenase (SDH) complex as new targets of miR‐142‐5p and provided evidence that Th17–miR‐142‐5p‐dependent reduced expression of SDHC and SDHD mediated enhanced migration and invasion of cancer cells using small interfering RNAs (siRNAs) for SDHC and SDHD, and miR‐142‐5p inhibitors. Consistently, patients exhibited high levels of succinate in their serum associated with lymph node metastases and diminished expression of SDHD in patient biopsies correlated with increased numbers of Th17 cells. Correspondingly, a combination of weak or negative SDHD expression and a ratio of Th17/CD4+ T cells > 43.90% in situ was associated with reduced recurrence‐free survival. In summary, we unraveled a previously unknown molecular mechanism by which Th17 cells promote cervical cancer progression and suggest evaluation of Th17 cells as a potential target for immunotherapy in cervical cancer.

Abstract Objective This study aimed to evaluate glymphatic system function in temporal lobe epilepsy (TLE) patients with hippocampal sclerosis (HS) in comparison to healthy controls, using diffusion tensor imaging (DTI)‐analysis along the perivascular space (ALPS) method. We hypothesized that there is glymphatic system dysfunction in TLE patients with HS. Methods We retrospectively enrolled 25 TLE patients with HS and 26 age‐ and sex‐matched healthy controls. All participants underwent DTI with the same 3T magnetic resonance imaging scanner, and the DTI‐ALPS index was calculated. We evaluated the differences in the DTI‐ALPS index between TLE patients with HS and healthy controls. Moreover, we evaluated the correlation between the DTI‐ALPS index and clinical characteristics of epilepsy, including age, age at seizure onset, duration of epilepsy, and number of anti‐seizure medications (ASMs). Results There was a difference in the DTI‐ALPS index between TLE patients with HS and healthy controls. The DTI‐ALPS index in TLE patients with HS was lower than that in healthy controls (1.497 vs. 1.668, P = .015). However, there was no difference in the DTI‐ALPS index between the newly diagnosed TLE patients with HS and the chronic TLE patients with HS. The DTI‐ALPS index was negatively correlated with age (r = −0.420, P = .036). However, the DTI‐ALPS index was not correlated with other clinical characteristics, including age at seizure onset, duration of epilepsy, and number of ASMs. Significance Our findings showed that the DTI‐ALPS index was significantly lower in TLE patients with HS than in healthy controls, indicating the presence of glymphatic system dysfunction in TLE patients with HS. Our study also suggests that the DTI‐ALPS method may be useful for evaluating glymphatic system function in epilepsy.

Cervical cancer therapy is still a major clinical challenge, as patients substantially differ in their response to standard treatments, including chemoradiotherapy (CRT). During cervical carcinogenesis, T‐helper (Th)‐17 cells accumulate in the peripheral blood and tumor tissues of cancer patients and are associated with poor prognosis. In this prospective study, we find increased Th17 frequencies in the blood of patients after chemoradiotherapy and a post‐therapeutic ratio of Th17/CD4+ T cells > 8% was associated with early recurrence. Furthermore, Th17 cells promote resistance of cervical cancer cells toward CRT, which was dependent on the AKT signaling pathway. Consistently, patients with high Th17 frequencies in pretherapeutic biopsies exhibit lower response to primary CRT. This work reveals a key role of Th17 cells in CRT resistance and elevated Th17 frequencies in the blood after CRT correspond with early recurrence. Our results may help to explain individual treatment responses of cervical cancer patients and suggest evaluation of Th17 cells as a novel predictive biomarker for chemoradiotherapy responses and as a potential target for immunotherapy in cervical cancer.

Abstract Introduction The aim of this study was to investigate alterations of the glymphatic system function in patients with cluster headache. Methods We enrolled patients with cluster headache and healthy controls, and they underwent brain magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI). We used the MRIcron and DSI studio programs for DTI preprocessing and DTI analysis with perivascular space (DTI‐ALPS) index calculation. Results Fourteen patients with cluster headache and 23 healthy controls were enrolled. The DTI‐ALPS indexes of the groups were significantly different. The DTI‐ALPS index for the patients with cluster headache was lower than that for the healthy controls (1.586 vs. 1.786, p = 0.044). There was a significant negative correlation between the DTI‐ALPS index and age in the patients with cluster headache (r = −0.549, p = 0.042). However, the DTI‐ALPS index was not associated with other clinical characteristics, including disease duration and headache intensity (r = −0.405, p = 0.150; r = −0.048, p = 0.869, respectively). Conclusion Patients with cluster headache had a lower DTI‐ALPS index than the healthy controls; this might indicate glymphatic system dysfunction in the patients with cluster headache. Further research is required to determine whether glymphatic system dysfunction is related to the pathophysiology of cluster headache.

Background Left ventricular (LV) involvement is frequently observed in arrhythmogenic cardiomyopathy (ACM). We investigated the association of LV myocardial assessment using cardiac magnetic resonance (CMR) with clinical outcomes including heart failure (HF)‐related events in ACM. Methods and Results We retrospectively analyzed 60 patients with ACM between 2005 and 2020 according to the 2010 Task Force Criteria and assessed HF‐related events (HF hospitalization, heart transplantation, and cardiac death) and ventricular tachycardia events. We analyzed CMR findings including late gadolinium enhancement (LGE) in all subjects and obtained mapping values (native T1, extracellular volume, and T2) on 30 (50%) patients out of them. Among the study population (mean age 49 years, 77% male), 41 (68%) patients had LV LGE. During a median follow‐up of 34 months, there were 13 (22%) HF‐related events, and 20 (30%) ventricular tachycardia events. Kaplan‐Meier survival analysis revealed that HF‐related events occurred only in patients with LV LGE (+) (versus LV LGE (‐), log‐rank P=0.006), and the events were not significantly different regarding right ventricular LGE (log‐rank P>0.999). When categorized by median value for each mapping parameter, HF‐related events occurred more in patients with higher native T1 (versus lower native T1, log‐rank P=0.002), and higher T2 (versus lower T2, log‐rank P=0.002), higher extracellular volume (versus lower extracellular volume, log‐rank P=0.002). However, regarding ventricular tachycardia events, there were no significant differences according to these CMR markers. Conclusions LV myocardial assessment using CMR with LGE imaging and native T1, T2, and extracellular volume markers were significantly associated with HF‐related event risk in patients with ACM.

Abstract With the timely advent of the electric vehicle era, where battery stability has emerged as a major issue, all‐solid‐state batteries (ASSBs) have attracted significant attention as the game changer owing to their high stability. However, despite the introduction of a densely packed solid electrolyte (SE) layer, when Li is used to increase the energy density of the cell, the short‐circuit problem caused by Li protrusion is unavoidable. Furthermore, most strategies to control nonuniform Li growth are so complicated that they hinder the practical application of ASSBs. To overcome these limitations, this study proposes an Ag‐Li alloy anode via mass‐producible roll pressing method. Unlike previous studies reporting solid‐solution‐based metal alloys containing a small amount of lithiophilic Ag, the in situ formed and Ag‐enriched Ag‐Li intermetallic layer mitigates uneven Li deposition and maintains a stable SE/Ag‐Li interface, facilitating reversible Li operation. Contrary to Li cells showing frequent initial short‐circuit, the cell incorporating the Ag‐Li anode exhibits a better capacity retention of 94.3% for 140 cycles, as well as stable cycling even under 12 C. Through a facile approach enabling the fabrication of a large‐area anode with controllable Li growth, this study provides practical insight for developing ASSBs with stable cyclabilities.

Abstract In adult patients with relapsed or refractory (R/R) Philadelphia chromosome‐negative (Ph‐negative) B‐cell presursor acute lymphoblastic leukemia (BCP‐ALL), complete remission (CR) and overall survival (OS) rates are poor. We analyzed treatment outcomes and prognostic factors for 32 adult patients with R/R Ph‐negative BCP‐ALL who received blinatumomab at first salvage. Patients who achieved CR proceeded to allogeneic hematopoietic cell transplantation (allo‐HCT). At the time of blinatumomab treatment, 11 patients (34.3%) were primary refractory, 10 (31.4%) had relapsed with first CR duration (CRD1) ≥12 months, and 11 (34.3%) had relapsed with CRD1

Abstract Ibrutinib is highly effective in patients with relapsed or refractory mantle cell lymphoma (MCL) in major clinical trials. Although there has been a dramatic improvement in survival outcomes in the salvage setting, nonresponders to ibrutinib have a bleak prognosis. Therefore, this retrospective study was conducted to identify the most appropriate therapeutic strategy and prognosis‐related factors to predict the response of patients with relapsed or refractory MCL to ibrutinib monotherapy. Thirty‐three consecutive refractory or relapsed MCL patients treated with ibrutinib were analyzed in this study. The median overall survival (OS) and progression‐free survival (PFS) after initiation of ibrutinib were 35.1 months and 27.4 months, respectively. Risk factor analysis showed that high risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI) and nonresponse to ibrutinib at the first three cycles were significantly associated with inferior OS. Poor PFS was associated with high‐risk biologic MIPI, prior bendamustine exposure, and nonresponse to ibrutinib during the first three cycles. After ibrutinib failure, primary nonresponders had poorer OS and PFS than inconsistent responders. The overall response rate for the first salvage therapy was only 33%, with a median TTP of 3.2 months. There was no effective therapeutic strategy except for allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Although ibrutinib responders exhibited favorable survival outcomes, nonresponders had a dismal prognosis. To overcome these limitations, it may be necessary to modify therapeutic strategies, such as selecting inconsistent responders for earlier allo‐HSCT.

Abstract Acute myocarditis and hyperthyroidism are common diseases that often present in young, otherwise healthy patients. Autoimmunity is central to the pathogenesis of both. Patients presenting with acute myocarditis should be screened for symptoms of hyperthyroidism, and physicians should consider screening for myocarditis in patients with hyperthyroidism and persistent cardiac symptoms.

Angiogenesis plays a critical role in embryo development, tissue repair, tumor growth and wound healing. In the present study, we investigated the role of the serine/threonine kinase Akt in angiogenesis. Silencing of Akt1 in human umbilical vein endothelial cells significantly inhibited vascular endothelial growth factor (VEGF)‐induced capillary‐like tube formation. Mice lacking Akt1 exhibited impaired retinal angiogenesis with delayed endothelial cell (EC) proliferation. In addition, VEGF‐induced corneal angiogenesis and tumor development were significantly inhibited in mice lacking Akt1. Loss of Akt1 resulted in reduced angiogenic sprouting, as well as the proliferation of ECs and mural cells. Addition of culture supernatant of vascular smooth muscle cells (VSMCs) in which Akt1 was silenced suppressed tube formation, the stability of preformed tubes and the proliferation of ECs. In addition, attachment of VSMCs to ECs was significantly reduced in cells in which Akt1 was silenced. Mural cell coverage of retinal vasculature was reduced in mice lacking Akt1. Finally, mice lacking Akt1 showed severe retinal hemorrhage compared to the wild‐type. These results suggest that the regulation of EC function and mural cell coverage by Akt1 is important for blood vessel maturation during angiogenesis.

Abstract Introduction Several lines of evidence suggest that the amygdala–hippocampus is involved in the epileptogenic network of juvenile myoclonic epilepsy (JME). The aim of this study was to investigate the alterations in the individual nuclei of the amygdala and hippocampal subfields, and the intrinsic amygdala‐hippocampal network of patients with JME compared to healthy controls. Methods This retrospective study conducted at a single tertiary hospital involved 35 patients with newly diagnosed JME, and 34 healthy subjects. We calculated the individual structural volumes of 18 nuclei in the amygdala, and 38 hippocampal subfields using three‐dimensional volumetric T1‐weighted imaging and FreeSurfer program. We also performed an analysis of the intrinsic amygdala‐hippocampal global and local network based on these volumes using a graph theory and Brain Analysis using Graph Theory (BRAPH) program. We investigated the differences in these volumes and network measures between patients with JME and healthy controls. Results There were no significant volume differences in the nuclei of the amygdala and hippocampal subfields between patients with JME and healthy controls. However, we found significant differences in the global network between patients with JME and healthy controls. The mean clustering coefficient was significantly decreased in patients with JME compared to healthy controls (0.473 vs. 0.653, p = .047). In addition, specific regions in the hippocampal subfields showed significant differences in the local network between the two groups. The betweenness centrality of the right CA1‐head, right hippocampus–amygdala‐transition area, left hippocampal fissure, left fimbria, and left CA3‐head, was increased in patients with JME compared to healthy controls. Conclusion The intrinsic amygdala‐hippocampal global and local networks differed in patients with JME compared to healthy controls, which may be related to the pathogenesis of JME, and memory dysfunction in patients with JME.

Abstract Objectives The aim of this study was to investigate alterations in structural and functional brain connectivity between patients with end‐stage renal disease (ESRD) who were undergoing peritoneal dialysis (PD) and hemodialysis (HD). Methods We enrolled 40 patients with ESRD who were undergoing PD (20 patients) and HD (20 patients). We also enrolled healthy participants as a control group. All of the subjects underwent diffusion tensor imaging (DTI) and resting‐state functional magnetic resonance imaging (rs‐fMRI). Using data from the structural and functional connectivity matrix based on DTI and rs‐fMRI, we calculated several network measures using graph theoretical analysis. Results The measures of global structural connectivity were significantly different between the patients with ESRD who were undergoing PD and healthy subjects. The global efficiency and local efficiency in the patients with PD were significantly decreased compared with those in healthy participants. However, all of the measures of global structural connectivity in the patients with HD were not different from those in healthy participants. Conversely, in the global functional connectivity, the characteristic path length was significantly increased and the small‐worldness index was decreased in patients with HD. However, the measures of the global functional connectivity in the patients with PD were not different from those in healthy subjects. Conclusion This study revealed that alterations in structural and functional connectivity in patients who were undergoing PD and HD were different than those in healthy controls. These findings suggest that brain networks may be affected by different types of renal replacement therapy.

Abstract Deferasirox is an oral iron‐chelating agent having possible antileukemia and immune modulatory effects. Few reports have evaluated deferasirox in the setting of allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We investigated the impact of deferasirox after allo‐HSCT in acute myeloid leukemia (AML). Of 326 consecutive patients undergoing allo‐HSCT in remission, analysis of 198 patients not receiving deferasirox revealed the negative prognostic effect of hyperferritinemia (≥1000 ng/mL) before and after allo‐HSCT on survival mainly due to increase in relapse. Of 276 patients with hyperferritinemia at 1 month after allo‐HSCT, 128 patients (46%) received deferasirox. Deferasirox induced a faster decline in serum ferritin level with a manageable safety profile, which significantly reduced relapse rather than nonrelapse mortality, resulting in better survival compared to patients not receiving deferasirox. Of note, the deferasirox group had a significantly higher incidence of chronic graft‐vs‐host disease, indicating improved graft‐vs‐leukemia (GVL) effects evidenced by the presence of suppressed regulatory T cells and sustained higher proportion of NK cells in peripheral blood. This study firstly demonstrates the improved survival and restoration of GVL effects of patients with AML by deferasirox, which also clarifies the detrimental effect of hyperferritinemia through after allo‐HSCT.

Axillary nodal status is one of the most important prognostic factors in breast cancer. The lymph node ratio (LNR) has been suggested as an independent prognostic factor because the number of dissected and involved lymph nodes might differ across institutions. Neoadjuvant chemotherapy (NAC) has been the preferred treatment method for reducing tumor mass in the breast and axillary area. However, NAC can reduce total number of excised lymph nodes compared with upfront surgery. Therefore, an emerging question is whether axillary nodal status and LNR following NAC can accurately predict prognosis. We evaluated the prognostic value of axillary nodal status and LNR after NAC. A total of 236 patients were enrolled. Patients were divided into four groups according to the following cut-off values for LNR: 0 (n = 107), 0.01–0.20 (n = 68), 0.21–0.65 (n = 50) and >0.65 (n = 11). Pathologic complete responses were observed in 16.9% of the overall cohort. In univariate analysis, pathologic N stage was a significant prognostic factor of disease free survival (DFS, p = 0.013) and overall survival (OS, p = 0.004). However, in multivariate analysis, hormone receptor status (p = 0.043) and LNR (p = 0.028) were significantly associated with DFS and LNR (p = 0.017) showed statistical significance for OS; however, pathologic N stage was no longer significantly associated with DFS or OS. Traditional nodal staging has been accepted as an important prognostic factor; however, our result indicated that the nodal ratio could be an alternative to pN staging as a prognostic factor after NAC in breast cancer. Keywords: Axilla, Breast, Neoadjuvant therapy, Lymph node, Survival

Abstract Although nilotinib has improved efficacy compared to imatinib, suboptimal response and intolerable adverse events (AEs) limit its effectiveness in many patients with chronic myeloid leukemia in chronic phase (CML‐CP). We investigated the 2‐year efficacy and safety of nilotinib and their relationships with plasma nilotinib concentrations (PNCs). In this open‐label, multi‐institutional phase 4 study, 110 Philadelphia chromosome‐positive CML‐CP patients were treated with nilotinib at a starting dose of 300 mg twice daily. Molecular responses (MRs) and AEs were monitored for up to 24 months. The 24‐month cumulative MR4.5 rate was evaluated as the primary endpoint. Plasma samples were collected from 94 patients to determine PNCs, and the per‐patient mean was used to categorize them into four mean PNC (MPNC) groups. Cumulative MR rates and safety were compared between groups. With a median follow‐up of 22.2 months, the 24‐month cumulative MR4.5 rate was 56.2% (95% confidence interval, 44.0%–8.3%), and the median time to MR4.5 was 23.3 months. There were no significant differences in the cumulative rates of major molecular response, MR4, and MR4.5 between MPNC groups. One patient died due to acute viral hepatitis, and two developed hematological or cytogenetic relapse, while no progression to accelerated or blast phase was observed. Safety results were consistent with previous studies with no new safety signal identified. Across the MPNC groups, there was no significant linear trend in the frequency of AEs. Nilotinib is highly effective for the treatment of CML‐CP with manageable AEs. The measurement of PNC has no predictive value for patient outcomes and is thus not found to be clinically useful. This study is registered with clinicaltrials.gov, Number NCT03332511.