TFE3/PI3K/Akt/mTOR Axis in Renal Cell Carcinoma Affects Tumor Microenvironment.

The role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in renal cell carcinoma (RCC) progression, metastasis, and resistance to therapies has not been investigated thoroughly. Transcription factor E3 (TFE3) expression is related to a poorer prognosis and tumor microenvironment in patients with RCC. This study aimed to determine the relationship between TFE3 and the PI3K/Akt pathway. TFE3 down-regulation was achieved by transient transfection of siRNA and shRNA in UOK146 cells. TFE3 overexpression was induced by transient transfection with pcDNA3.1 encoding the constitutively active form of TFE3. The cells were treated with mammalian target of rapamycin (mTOR) and PI3K inhibitors. Western blot was performed to detect TFE3, programmed death-ligand 1, phospho-Akt, and Akt. Phospho-Akt expression increased significantly upon TFE3 down-regulation, and decreased significantly upon up-regulation. When RCC cells were treated with a PI3K inhibitor (LY294002), TFE3 expression increased and phospho-Akt expression decreased. Data from this study indicate that TFE3 plays a role in the PI3K/Akt pathway in RCC. The results of this study suggest that PI3K/Akt inhibitors may aid in the treatment of patients with RCC by affecting the tumor microenvironment.

Timing of fractional flow reserve-guided complete revascularization in patients with ST-segment elevation myocardial infarction with multivessel disease: Rationale and design of the OPTION-STEMI trial.

BACKGROUND: Current guidelines recommend complete revascularization (CR) in hemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD). With regard to the timing of percutaneous coronary intervention (PCI) for non-infarct-related artery (non-IRA), recent randomized clinical trials have revealed that immediate CR was non-inferior to staged CR. However, the optimal timing of CR remains uncertain. The OPTION-STEMI trial compared immediate CR and in-hospital staged CR guided by fractional flow reserve (FFR) for intermediate stenosis of the non-IRA. METHODS: The OPTION-STEMI is a multicenter, investigator-initiated, prospective, open-label, non-inferiority randomized clinical trial. The study included patients with at least 1 non-IRA lesion with ≥50% stenosis by visual estimation. Patients fulfilling the inclusion criteria were randomized into 2 groups at a 1:1 ratio: immediate CR (i.e., PCI for the non-IRA performed during primary angioplasty) or in-hospital staged CR. In the in-hospital staged CR group, PCI for non-IRA lesions was performed on another day during the index hospitalization. Non-IRA lesions with 50%-69% stenosis by visual estimation were evaluated by FFR, whereas those with ≥70% stenosis was revascularized without FFR. The primary endpoint was the composite of all-cause death, non-fatal myocardial infarction, and all unplanned revascularization at 1 year after randomization. Enrolment began in December 2019 and was completed in January 2024. The follow-up for the primary endpoint will be completed in January 2025, and primary results will be available in the middle of 2025. CONCLUSIONS: The OPTION-STEMI is a multicenter, non-inferiority, randomized trial that evaluated the timing of in-hospital CR with the aid of FFR in patients with STEMI and MVD. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT04626882; and URL: https://cris.nih.go.kr. Unique identifier: KCT0004457.

The relationship between tumor-infiltrating neutrophils and clinical outcomes in patients with resectable hepatocellular carcinoma.

BACKGROUND: The impact of tumor-infiltrating neutrophils (TINs) on clinical outcomes has been reported in various cancer types, but their role in hepatocellular carcinoma (HCC) has not been fully evaluated. The aim of this study was to investigate the prognostic values for TINs in HCC patients undergoing curative resection. METHODS: We assessed immune markers (CD3, CD4, CD8, CD66b) using immunohistochemistry in 115 patients who underwent curative resection for HCC. We analyzed the prognostic values for tumor-infiltrating immune cells, including neutrophils, and other clinicopathological factors. RESULTS: In the Multivariate Cox analysis of overall survival (OS), alpha-fetoprotein (AFP) ≥ 100 ng/mL (hazard ratio (HR), 2.74, 95% confidence interval (CI), 1.17-6.44; P = 0.021) and Barcelona Clinic Liver Cancer (BCLC) B/C stage (HR, 3.98, 95% CI, 1.68-9.43; P = 0.020) were found to be independent poor prognostic factors in HCC patients undergoing resection. The presence of CD66b+TINs was observed in 66 (57.4%) patients. However, CD66b+TINs were not associated with recurrence-free survival and OS. CONCLUSIONS: Our study identified low CD66b+TINs in resectable HCC, and CD66b+ TINs did not have a significant role for the clinical outcomes of patients undergoing curative resection. The results suggest that TINs may play a role in more advanced stages of HCC.

TOPORS-mediated RAD51 SUMOylation facilitates homologous recombination repair.

Homologous recombination (HR) is critical for error-free repair of DNA double-strand breaks. Chromatin loading of RAD51, a key protein that mediates the recombination, is a crucial step in the execution of the HR repair. Here, we present evidence that SUMOylation of RAD51 is crucial for the RAD51 recruitment to chromatin and HR repair. We found that topoisomerase 1-binding arginine/serine-rich protein (TOPORS) induces the SUMOylation of RAD51 at lysine residues 57 and 70 in response to DNA damaging agents. The SUMOylation was facilitated by an ATM-induced phosphorylation of TOPORS at threonine 515 upon DNA damage. Knockdown of TOPORS or expression of SUMOylation-deficient RAD51 mutants caused reduction in supporting normal RAD51 functions during the HR repair, suggesting the physiological importance of the modification. We found that the SUMOylation-deficient RAD51 reduces the association with its crucial binding partner BRCA2, explaining its deficiency in supporting the HR repair. These findings altogether demonstrate a crucial role for TOPORS-mediated RAD51 SUMOylation in promoting HR repair and genomic maintenance.

53BP1-ACLY-SLBP-coordinated activation of replication-dependent histone biogenesis maintains genomic integrity.

p53-binding protein 1 (53BP1) regulates the DNA double-strand break (DSB) repair pathway and maintains genomic integrity. Here we found that 53BP1 functions as a molecular scaffold for the nucleoside diphosphate kinase-mediated phosphorylation of ATP-citrate lyase (ACLY) which enhances the ACLY activity. This functional association is critical for promoting global histone acetylation and subsequent transcriptome-wide alterations in gene expression. Specifically, expression of a replication-dependent histone biogenesis factor, stem-loop binding protein (SLBP), is dependent upon 53BP1-ACLY-controlled acetylation at the SLBP promoter. This chain of regulation events carried out by 53BP1, ACLY, and SLBP is crucial for both quantitative and qualitative histone biogenesis as well as for the preservation of genomic integrity. Collectively, our findings reveal a previously unknown role for 53BP1 in coordinating replication-dependent histone biogenesis and highlight a DNA repair-independent function in the maintenance of genomic stability through a regulatory network that includes ACLY and SLBP.

SIAH2 regulates DNA end resection and replication fork recovery by promoting CtIP ubiquitination.

Human CtIP maintains genomic integrity primarily by promoting 5' DNA end resection, an initial step of the homologous recombination (HR). A few mechanisms have been suggested as to how CtIP recruitment to damage sites is controlled, but it is likely that we do not yet have full understanding of the process. Here, we provide evidence that CtIP recruitment and functioning are controlled by the SIAH2 E3 ubiquitin ligase. We found that SIAH2 interacts and ubiquitinates CtIP at its N-terminal lysine residues. Mutating the key CtIP lysine residues impaired CtIP recruitment to DSBs and stalled replication forks, DSB end resection, overall HR repair capacity of cells, and recovery of stalled replication forks, suggesting that the SIAH2-induced ubiquitination is important for relocating CtIP to sites of damage. Depleting SIAH2 consistently phenocopied these results. Overall, our work suggests that SIAH2 is a new regulator of CtIP and HR repair, and emphasizes that SIAH2-mediated recruitment of the CtIP is an important step for CtIP's function during HR repair.

Transradial Versus Transfemoral Access for Bifurcation Percutaneous Coronary Intervention Using Second-Generation Drug-Eluting Stent.

BACKGROUND: The benefits of transradial access (TRA) over transfemoral access (TFA) for bifurcation percutaneous coronary intervention (PCI) are uncertain because of the limited availability of device selection. This study aimed to compare the procedural differences and the in-hospital and long-term outcomes of TRA and TFA for bifurcation PCI using second-generation drug-eluting stents (DESs). METHODS: Based on data from the Coronary Bifurcation Stenting Registry III, a retrospective registry of 2,648 patients undergoing bifurcation PCI with second-generation DES from 21 centers in South Korea, patients were categorized into the TRA group (n = 1,507) or the TFA group (n = 1,141). After propensity score matching (PSM), procedural differences, in-hospital outcomes, and device-oriented composite outcomes (DOCOs; a composite of cardiac death, target vessel-related myocardial infarction, and target lesion revascularization) were compared between the two groups (772 matched patients each group). RESULTS: Despite well-balanced baseline clinical and lesion characteristics after PSM, the use of the two-stent strategy (14.2% vs. 23.7%, P = 0.001) and the incidence of in-hospital adverse outcomes, primarily driven by access site complications (2.2% vs. 4.4%, P = 0.015), were significantly lower in the TRA group than in the TFA group. At the 5-year follow-up, the incidence of DOCOs was similar between the groups (6.3% vs. 7.1%, P = 0.639). CONCLUSION: The findings suggested that TRA may be safer than TFA for bifurcation PCI using second-generation DESs. Despite differences in treatment strategy, TRA was associated with similar long-term clinical outcomes as those of TFA. Therefore, TRA might be the preferred access for bifurcation PCI using second-generation DES. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03068494.

Automated Pavement Condition Index Assessment with Deep Learning and Image Analysis: An End-to-End Approach.

The degradation of road pavements due to environmental factors is a pressing issue in infrastructure maintenance, necessitating precise identification of pavement distresses. The pavement condition index (PCI) serves as a critical metric for evaluating pavement conditions, essential for effective budget allocation and performance tracking. Traditional manual PCI assessment methods are limited by labor intensity, subjectivity, and susceptibility to human error. Addressing these challenges, this paper presents a novel, end-to-end automated method for PCI calculation, integrating deep learning and image processing technologies. The first stage employs a deep learning algorithm for accurate detection of pavement cracks, followed by the application of a segmentation-based skeleton algorithm in image processing to estimate crack width precisely. This integrated approach enhances the assessment process, providing a more comprehensive evaluation of pavement integrity. The validation results demonstrate a 95% accuracy in crack detection and 90% accuracy in crack width estimation. Leveraging these results, the automated PCI rating is achieved, aligned with standards, showcasing significant improvements in the efficiency and reliability of PCI evaluations. This method offers advancements in pavement maintenance strategies and potential applications in broader road infrastructure management.

Impact of Neoadjuvant Chemotherapy (NAC) on Biomarker Expression in Breast Cancer.

Background and Objectives: This study aimed to explore biomarker change after NAC (neoadjuvant chemotherapy) and to investigate biomarker expression as a prognostic factor in patients with residual disease (RD) after NAC. Materials and Methods: We retrospectively evaluated 104 patients with invasive breast cancer, who underwent NAC and surgery at Pusan National University Hospital from 2015 to July 2022. The expression of the biomarker was assessed, and the overall survival (OS) and disease-free survival (DFS) were investigated. Results: After NAC, 24 patients (23.1%) out of 104 total patients had a pathological complete response (pCR). We found that changes in at least one biomarker were observed in 41 patients (51.2%), among 80 patients with RD. In patients with RD after NAC (n = 80), a subtype change was identified in 20 patients (25.0%). Any kind of change in the HER2 status was present 19 (23.7%) patients. The hormone receptor (HR)+/HER2+ subtype was significantly associated with better disease-free survival (DFS) (HR, 0.13; 95% CI, 0.02-0.99; p = 0.049). No change in p53 was associated with better DFS, and negative-to-positive change in p53 expression after NAC was correlated with worse DFS (p < 0.001). Negative-to-positive change in p53 was an independent, worse DFS factor in the multivariate analysis (HR,18.44; 95% CI, 1.86-182.97; p = 0.013). Conclusions: Biomarker change and subtype change after NAC were not infrequent, which can affect the further treatment strategy after surgery. The expression change of p53 might have a prognostic role. Overall, we suggest that the re-evaluation of biomarkers after NAC can provide a prognostic role and is needed for the best decision to be made on further treatment.

A uniform conditioning regimen of busulfan, fludarabine, and antithymocyte globulin for allogeneic haematopoietic cell transplantation from haploidentical family, matched sibling, or unrelated donors-A single-centre, prospective, explorative study.

In a prospective, explorative study, the donor-source difference of haploidentical family (HF), matched sibling (MS), and unrelated donors (UD) was evaluated for the outcome of haematopoietic cell transplantations (HCT) in 101 patients with acute myeloid leukaemia (AML) in complete remission (CR). To eliminate compounding effects, a uniform conditioning regimen containing antithymocyte globulin (ATG) was used. After transplantation, there was a significantly higher cumulative incidence of acute graft-versus-host disease (GVHD) in HF-HCT patients (49%, 7%, and 16% for HF-, MS- and UD-HCT respectively; p < 0.001). A quarter of acute GVHD cases observed in HF-HCT patients occurred within three days of engraftment and were characterized by diffuse skin rash, fever, weight gain, and hypoalbuminaemia. This peri-engraftment acute GVHD was not observed in MS-HCT or UD-HCT patients. Additionally, a significantly higher proportion of HF-HCT patients achieved complete donor chimaerism in the peripheral mononuclear cells at one month (88%, 46%, and 69% for HF-, MS- and UD-HCT respectively; p = 0.001). There was no significant difference in engraftment, chronic GVHD, leukaemia recurrence, non-relapse mortality, and patient survival. In patients with AML in CR who received HCT using ATG-containing conditioning, stronger donor-patient alloreactivity was observed in HF-HCT, in terms of increased acute GVHD and higher likelihood of complete donor chimaerism.

Impact of guideline-directed medical therapy on 5-year mortality in patients with newly diagnosed peripheral artery disease.

OBJECTIVE: Current guidelines recommend that patients with peripheral artery disease (PAD) should be treated with antithrombotic agents, renin-angiotensin-system blockers, and statins. However, the clinical impact of guideline-directed medical therapy (GDMT) on long-term mortality in patients with newly diagnosed PAD remains unclear. We aimed to investigate the prevalence of GDMT and evaluate 5-year mortality according to GDMT after PAD diagnosis. METHODS: This retrospective cohort study, using nationwide health insurance claims data in Korea, included patients newly diagnosed with PAD between 2006 and 2015. GDMT was defined as the use of all drugs, including antithrombotic agents, renin-angiotensin-system blockers, and statins, within 3 months of PAD diagnosis. The primary endpoint was all-cause mortality. RESULTS: We investigated 19,561 newly diagnosed patients with PAD without proven cardiovascular disease. Among the study population, 4378 patients (22.4%) were categorized in the GDMT and 15,183 (77.6%) in the non-GDMT groups. During the 5-year follow-up, GDMT showed a lower incidence of all-cause mortality than that of non-GDMT (2.8% vs 4.8%; adjusted hazard ratio, 0.329; 95% confidence interval, 0.257-0.421; P < .001). Even in the propensity-matched population, GDMT showed a lower mortality rate than non-GDMT (hazard ratio, 0.283; 95% confidence interval, 0.217-0.370; P < .001). As the number of guideline-recommended drugs increased, the mortality rate decreased proportionately. CONCLUSIONS: After PAD diagnosis, GDMT was associated with a lower incidence of mortality regardless of proven cardiovascular disease. This retrospective analysis showed an insufficient prevalence of GDMT among patients with PAD in real-world practice.

Natural Killer Cell Activity Test Helps to Suspect Aggressive Natural Killer Cell Leukemia - Diagnostic Challenge.

Aggressive natural killer cell leukemia (ANKL) is a rare disease with an aggressive clinical course. We aimed to assess the clinicopathological characteristics of the difficult to diagnose ANKL. During ten years, nine patients with ANKL were diagnosed. All the patients exhibited aggressive clinical course and underwent the BM study to rule out lymphoma and hemophagocytic lymphohistiocytosis (HLH). BM examination showed varying degrees of infiltration of neoplastic cells, which were mainly positive for CD2, CD56, cytoplasmic CD3 and EBV in situ hybridization. Five BM aspirates showed histiocytic proliferation with active heomphagocytosis. Normal or increased NK cell activity test results were obtained from 3 patients who were available for testing. Four had multiple BM studies until diagnosis. An aggressive clinical course and positive EBV in situ hybridization, often with associated secondary HLH, should raise the suspicion of an ANKL. Conducting additional supplementary tests such as NK cell activity and NK cell proportion would be helpful for the diagnosis of ANKL.

Histological subtypes of hepatocellular carcinoma: Their clinical and prognostic significance.

Assigning a hepatocellular carcinoma (HCC) to an appropriate subtype is important because this guarantees the diagnosis and treatment and allows decisions regarding the prognosis of the patient. HCC subtyping is usually based on the World Health Organization (WHO) classification and the 2019 fifth edition is the latest version. However, the WHO classification system is still in evolution and has limited clinical relevance. We aimed to evaluate the clinical relevance of HCC subtyping and to reappraise some of the major subtypes of HCC. Our archived cases (n = 589) were reclassified according to the 2019 WHO system. The percentage of each subtype was mostly similar to that in the WHO classification. However, on the contrary to the 2019 WHO system, clear cell type HCC was associated with more frequent recurrence or metastasis. Meanwhile, macrotrabecular massive HCC was related to poor prognosis as demonstrated in the 2019 WHO system and should be described in the pathology report. For steatohepatitic HCC, there is a debate on whether it is a true subtype because the steatohepatitis morphology may or may not be present in the background liver. In our study, 44 % of steatohepatitic HCCs (n = 19/43) presented underlying steatohepatitis. Additionally, the background cirrhosis did not influence survival in the HCC patients, although the 2019 WHO system indicates the presence of cirrhosis as a poor prognostic factor. In conclusion, although it is not perfect yet, HCC subtyping based on the 2019 WHO system provides valuable information to manage patients with HCC.

Minimum Detection Concentration of Hydrogen in Air Depending on Substrate Type and Design of the 3ω Sensor.

Hydrogen has emerged as a promising carbon-neutral fuel source, spurring research and development efforts to facilitate its widespread adoption. However, the safe handling of hydrogen requires precise leak detection sensors due to its low activation energy and explosive potential. Various detection methods exist, with thermal conductivity measurement being a prominent technique for quantifying hydrogen concentrations. However, challenges remain in achieving high measurement sensitivity at low hydrogen concentrations below 1% for thermal-conductivity-based hydrogen sensors. Recent research explores the 3ω method's application for measuring hydrogen concentrations in ambient air, offering high spatial and temporal resolutions. This study aims to enhance hydrogen leak detection sensitivity using the 3ω method by conducting thermal analyses on sensor design variables. Factors including substrate material, type, and sensor geometry significantly impact the measurement sensitivity. Comparative evaluations consider the minimum detectable hydrogen concentration while accounting for the uncertainty of the 3ω signal. The proposed suspended-type 3ω sensor is capable of detecting hydrogen leaks in ambient air and provides real-time measurements that are ideal for monitoring hydrogen diffusion. This research serves to bridge the gap between precision and real-time monitoring of hydrogen leak detection, promising significant advancements in the related safety applications.

Clinical implications and genetic features of clonal cytopenia of undetermined significance compared to lower-risk myelodysplastic syndrome.

Clonal cytopenia of undetermined significance (CCUS) is characterized by persistent cytopenias with genetic aberrations, which do not meet the diagnostic criteria for myelodysplastic syndrome (MDS). We aimed to compare the clinical and genetic characteristics of CCUS with lower-risk MDS and identify patients with CCUS with a high risk of progression. We performed targeted sequencing of bone marrow (BM) samples from patients with idiopathic cytopenia of undetermined significance (ICUS) (n = 139) and MDS (n = 226). Overall survival (OS) of patients with CCUS (n = 78) was worse than non-clonal ICUS (n = 61) and superior to lower-risk MDS (n = 99). Patients with CCUS showed similar characteristics to those with lower-risk MDS, except for higher haemoglobin, lower BM cellularity, and less frequent SF3B1 mutations. Lower haemoglobin, DDX41 (biallelic germline and somatic), ETV6, and RUNX1 mutations were independent prognostic factors for worse OS. Lower haemoglobin and DDX41 mutations were also associated with lower progression-free survival. Patients with CCUS with high-risk features showed similar or worse OS than patients with lower-risk MDS. Our findings suggest that patients with CCUS having certain clinical or genetic features should be regarded and treated as lower-risk MDS despite lacking significant dysplasia or MDS-associated chromosomal abnormalities.

mTOR Inhibition Increases Transcription Factor E3 (TFE3) Activity and Modulates Programmed Death-Ligand 1 (PD-L1) Expression in Translocation Renal Cell Carcinoma.

The efficacy of programmed death ligand (PD-L)-1/PD-1 checkpoint blockade in renal cell carcinoma (RCC) remains unknown. The effects of mTOR inhibitors are uncertain, and patients may develop resistance to them. The limited understanding of cancer cell-intrinsic mTOR-mediated pathways remains a challenge in developing effective treatments. Whether transcription factor (TF)-E3 regulates PD-L1 expression and the tumor microenvironment was investigated, and the effects of an mammalian target of rapamycin (mTOR) inhibitor on translocation RCC were explored. TFE3 was overexpressed in clear cell RCC cell lines, and PD-L1 expression was analyzed by Western blot analysis. PD-L1 activity in translocation RCC was analyzed in relation to TFE3 expression via TFE3 knockdown and treatment with an mTOR inhibitor. The results were correlated with the gene expression profile, evaluated using digital multiplex analysis. TFE3 and PD-L1 expression were positively correlated in RCC cells. TFE3 overexpression was associated with the expression of PD-L1 in RCC. Furthermore, mTOR inhibition was associated with enhanced PD-L1 expression via TFE3 activation in translocation RCC. These data support the feasibility of combination therapy based on mTOR inhibition and PD-L1 blockade as a novel strategy for the treatment of patients with translocation RCC.

Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia.

DDX41 mutations are associated with hematologic malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but the incidence in idiopathic cytopenia of undetermined significance (ICUS) is unknown. We investigated the incidence, genetic characteristics, and clinical features of DDX41 mutations in Korean patients with ICUS, MDS, or AML. We performed targeted deep sequencing of 61 genes including DDX41 in 457 patients with ICUS (n=75), MDS (n=210), or AML (n=172). Germline DDX41 mutations with causality were identified in 28 (6.1%) patients, of whom 27 (96.4%) had somatic mutations in the other position of DDX41. Germline origins of the DDX41 mutations were confirmed in all of the 11 patients in whom germline-based testing was performed. Of the germline DDX41 mutations, p.V152G (n=10) was most common, followed by p.Y259C (n=8), p.A500fs (n=6), and p.E7* (n=3). Compared with non-mutated patients, patients with a DDX41 mutation were more frequently male, older, had a normal karyotype, low leukocyte count, and hypocellular marrow at diagnosis. Three of the four ICUS patients with germline DDX41 mutations progressed to MDS. The incidence of DDX41 mutations in Korean patients was high and there was a distinct mutation pattern, in that p.V152G was a unique germline variant. ICUS harboring germline DDX41 mutations may be regarded as a hereditary myeloid neoplasm. Germline DDX41 mutations are not uncommon and should be explored when treating patients with myeloid malignancies.

Analysis of measurement changes in pelvic incidence according to pelvic rotation using a three-dimensional model.

BACKGROUND: Pelvic incidence (PI) is used as a key parameter in surgical correction of adult spinal deformity (ASD). However, reflecting the exact center or inclination of the three-dimensional anatomical structures on the two-dimensional (2D) sagittal radiographs is limited, resulting in measurement errors. Therefore, we evaluated whether there is a change in PI measurement according to the actual rotation of the pelvis, and conducted a study on a more accurate method for PI measurement using 2D sagittal radiographs. METHODS: From 2014 to 2015, the data of 30 patients who visited our outpatient clinic were analyzed retrospectively. CT scans including those of the lower lumbar spine, pelvis, and both femurs in the DICOM format were imported to Mimics Research 17.0 (Materialise NV, Belgium), SolidWorks (Dassault systems, France), and AutoCAD 2014 (AUTODESK, US). The changes in PI according to vertical and horizontal pelvic rotations were evaluated. RESULTS: The average PIs according to the horizontal pelvic rotations measured on AutoCAD with 0°, 5°, 10°, 15°, 20°, 25°, 30°, 35°, and 40° were 48.8°, 48.7°, 48.3°, 47.8°, 46.9°, 45.6°, 44.0°, 42.2°, and 39.9°, respectively. The PI with an acceptable error of 6° on radiographs was 35° in the horizontal pelvic rotation. The average PIs according to the vertical pelvic rotations measured on AutoCAD with 0°, 5°, 10°, 15°, 20°, 25°, 30°, 35°, and 40° were 48.8°, 49.0°, 49.5°, 50.2°, 51.3°, 52.7°, 54.4°, 56.6°, and 59.4°, respectively. The PI with an acceptable error of 6° on radiographs was 30° in the vertical pelvic rotation. CONCLUSIONS: This study revealed that the PI value could differ from the actual anatomical value due to the horizontal and vertical rotation of the pelvis while acquiring the radiograph. Regarding whole-spine lateral radiographs, errors in PI measurement may occur due to pelvic rotation or nonvertical projection of X-rays. In the standing pelvic lateral radiographs, ensuring superposition of the femoral heads at the center and obtaining the straight sacral endplate by referring to CT or magnetic resonance imaging would be a more accurate measurement method to define PI.

Anti-cancer effects of fenbendazole on 5-fluorouracil-resistant colorectal cancer cells.

Benzimidazole anthelmintic agents have been recently repurposed to overcome cancers resistant to conventional therapies. To evaluate the anti-cancer effects of benzimidazole on resistant cells, various cell death pathways were investigated in 5-fluorouracil-resistant colorectal cancer cells. The viability of wild-type and 5-fluorouracil-resistant SNU-C5 colorectal cancer cells was assayed, followed by Western blotting. Flow cytometry assays for cell death and cell cycle was also performed to analyze the anti-cancer effects of benzimidazole. When compared with albendazole, fenbendazole showed higher susceptibility to 5-fluorouracil-resistant SNU-C5 cells and was used in subsequent experiments. Flow cytometry revealed that fenbendazole significantly induces apoptosis as well as cell cycle arrest at G2/M phase on both cells. When compared with wild-type SNU-C5 cells, 5-fluorouracil-resistant SNU-C5 cells showed reduced autophagy, increased ferroptosis and ferroptosis-augmented apoptosis, and less activation of caspase-8 and p53. These results suggest that fenbendazole may be a potential alternative treatment in 5-fluorouracil-resistant cancer cells, and the anticancer activity of fenbendazole does not require p53 in 5-fluorouracil-resistant SNU-C5 cells.

Busulfan, etoposide, cytarabine, and melphalan as a high-dose regimen for autologous stem cell transplantation in peripheral T-cell lymphomas.

Given the unsatisfactory survival in patients who received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) for peripheral T-cell lymphomas (PTCLs), we conducted a prospective trial of busulfan (Bu), etoposide (E), cytarabine (A), and melphalan (M) (BuEAM), including IV Bu instead of carmustine (BCNU) as in standard BEAM, as a high-dose regimen in such patients. This study evaluated the efficacy and toxicity of BuEAM as a high-dose regimen for ASCT in patients with T-cell lymphomas. The high-dose chemotherapy at seven centers in Korea included Bu (3.2 mg/kg IV qd from day 6 to day 5), E (200 mg/m2 IV bid on day 4 and day 3), A (1 g/m2 IV qd on day 4 and day 3), and M (140 mg/m2 IV qd on day 2). Eighty-one patients were enrolled in this study. The main subtypes were peripheral T-cell lymphoma, not other specified (n = 32, 39.5%), NK/T-cell lymphoma (n = 22, 27.5%), and angioimmunoblastic T-cell lymphoma (n = 12, 14.8%). Upfront and salvage ASCTs were performed in 65 (80.2%) and 16 (19.8%) patients, respectively. The disease status of the patients before ASCT was 54 patients (66.7%) with complete response and 27 patients (33.3%) with partial response. The common grade-III toxicities were anorexia (8.6%), diarrhea (7.4%), and stomatitis (4.9%). No veno-occlusive disorder was noted. Fifty-six (69.1%) and seven (8.6%) patients achieved complete and partial response, respectively, after ASCT, although 17 patients (21.0%) showed progressive disease. At a median follow-up duration of 49.3 months, the estimated 3-year progression-free survival and overall survival were 55.2% and 68.2% in all patients. The BuEAM high-dose regimen for ASCT was well tolerated and seemed to be effective in patients with T-cell lymphomas.