Multicenter Retrospective Analysis of Original versus Modified FOLFIRINOX in Metastatic Pancreatic Cancer: Results of the NAPOLEON Study.

INTRODUCTION: Original FOLFIRINOX (oFFX) is more toxic than other regimens for patients with metastatic pancreatic cancer (mPC); therefore, a modified FFX (mFFX) regimen with a reduced dosage has been used in Japanese clinical practice. However, very few studies have compared these two regimens. METHODS: This study was conducted as part of a multicenter retrospective study of 318 patients with mPC across 14 centers in Japan (NAPOLEON study). To control for potential bias and confounders, we conducted a propensity score-adjusted analysis of patient characteristics and clinical outcomes. RESULTS: oFFX and mFFX were administered to 48 and 54 patients. More patients with younger age and poorer performance status were included in the oFFX group. The overall survival (OS; median, 11.6 vs. 11.3 months; hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.60-1.40; p = 0.67), progression-free survival (PFS) (median, 6.3 vs. 5.7 months; HR, 0.85; 95% CI, 0.56-1.28; p = 0.44), and overall response rate (29 vs. 26%, p = 0.71) were not significantly different for the oFFX and mFFX groups. Thrombopenia and liver dysfunction were significantly more frequent with oFFX than with mFFX. The median received dose intensity of CPT-11 was higher with oFFX than with mFFX (299 vs. 270 mg/m2/week, p < 0.01). The propensity score-adjusted analysis revealed no statistically significant differences in OS and PFS between the two groups. CONCLUSION: In our data, there was no significant difference in efficacy between mFFX and oFFX, and mFFX has fewer adverse events.

Scoring model with serum albumin and CA19-9 for metastatic pancreatic cancer in second-line treatment: results from the NAPOLEON study.

BACKGROUND: Patients with metastatic pancreatic cancer refractory to first-line chemotherapy (CTx) have few treatment options. It is unclear what kind of patients could be brought about survival benefit by 2nd-line CTx after refractory to gemcitabine + nab-PTX (GnP) or FOLFIRINOX. METHODS: This analysis was conducted as part of a multicenter retrospective study of GnP or FOLFIRINOX in patients with metastatic pancreatic cancer. Excluding censored cases, 156 and 77 patients, respectively, received second-line chemotherapy (CTx) and best supportive care (BSC). Using prognostic factors for post-discontinuation survivals (PDSs) at the first-line determination in multivariate analysis, we developed a scoring system to demonstrate the benefit of second-line CTx. RESULTS: The second-line CTx group had a median PDS of 5.2 months, whereas the BSC group had a median PDS of 2.7 months (hazard ratio 0.42; 95% confidence interval [CI] 0.31-0.57; p < 0.01). According to the Cox regression model, serum albumin levels below 3.5 g/dL, and CA19-9 levels above 1000 U/mL were independent prognostic factors (p < 0.01). Serum albumin (≥ and < 3.5 g/dL allotted to scores 0 and 1) and CA19-9 (< and ≥ 1000 U/mL allotted to scores 0 and 1) at first-line determination were used to develop the scoring system. The PDSs of patients with scores of 0 and 1 were significantly better than those of the BSC group; however, there was no significant difference between the PDSs of patients with score 2 and the BSC group. CONCLUSION: The survival advantage of second-line CTx, was observed in patients with scores of 0 and 1 but not in those with score 2.

Angioarchitecture of the hemorrhagic developmental venous anomaly with stenosis of the collecting vein and cavernous malformation: a case report.

We herein report a case of developmental venous anomaly (DVA) with venous congestion caused by stenosis of the collecting vein that presented with intracerebral hemorrhage (ICH). A 74-year-old woman was referred to our hospital a few days after the onset of motor aphasia. Computed tomography (CT) and magnetic resonance imaging (MRI) showed ICH in the left frontal lobe. Angiography revealed DVA in the left frontal lobe in the late venous phase. Stenosis of the collecting vein of DVA at the entrance to the superior sagittal sinus was detected and accompanied by cavernous malformation (CM) beside DVA. Cone-beam CT revealed the absence of the left septal vein and hypoplastic transverse caudate veins. The patient was treated by blood pressure management and no additional neurological symptoms were detected. DVA develops to compensate for the absence of pial or deep venous systems, and generally benign and clinically asymptomatic. However, the outflow restriction of DVA causes chronic venous hypertension and the formation of CM. These abnormalities are considered to occur during post-natal life and may result in ICH. The risk of hemorrhage needs to be considered in cases of DVA with restricted venous outflow or CM.

Prognostic nomogram for patients with unresectable pancreatic cancer treated with gemcitabine plus nab-paclitaxel or FOLFIRINOX: A post-hoc analysis of a multicenter retrospective study in Japan (NAPOLEON study).

BACKGROUND: No reliable nomogram has been developed until date for predicting the survival in patients with unresectable pancreatic cancer undergoing treatment with gemcitabine plus nab-paclitaxel (GnP) or FOLFIRINOX. METHODS: This analysis was conducted using clinical data of Japanese patients with unresectable pancreatic cancer undergoing GnP or FOLFIRINOX treatment obtained from a multicenter study (NAPOLEON study). A Cox proportional hazards model was used to identify the independent prognostic factors. A nomogram to predict 6-, 12-, and 18-month survival probabilities was generated, validated by using the concordance index (C-index), and calibrated by the bootstrapping method. And then, we attempted risk stratification for survival by classifying the patients according to the sum of the scores on the nomogram (total nomogram points). RESULTS: A total of 318 patients were enrolled. A prognostic nomogram was generated using data on the Eastern Cooperative Oncology Group performance status, liver metastasis, serum LDH, serum CRP, and serum CA19-9. The C-indexes of the nomogram were 0.77, 0.72 and 0.70 for 6-, 12-, and 18-month survival, respectively. The calibration plot showed optimal agreement at all points. Risk stratification based on tertiles of the total nomogram points yielded clear separations of the survival curves. The median survival times in the low-, moderate-, and high-risk groups were 15.8, 12.8 and 7.8 months (P<0.05), respectively. CONCLUSIONS: Our nomogram might be a convenient and inexpensive tool to accurately predict survival in Japanese patients with unresectable pancreatic cancer undergoing treatment with GnP or FOLFIRINOX, and will help clinicians in selecting appropriate therapeutic strategies for individualized management.

Stroke Risk in Patients with Suspected Transient Ischemic Attacks with Focal and Nonfocal Symptoms: A Prospective Study.

OBJECTIVES: The aim was to investigate triage methods for suspected transient ischemic attacks (TIAs) with focal or nonfocal symptoms. MATERIALS AND METHODS: In total, 350 patients with suspected TIAs were enrolled and followed for one year. Potential high-risk factors for TIAs, such as atrial fibrillation, carotid artery stenosis, crescendo TIA, and ABCD2 score ≥ 4, were evaluated. Patients were classified into 3 groups according to the initial neurological symptoms: focal, nonfocal, and mixed (both focal and nonfocal) groups. Stroke-free survival rates were compared via Kaplan-Meier analysis. RESULTS: Diffusion-weighted MRI (DWI) was performed for 89.8% of the patients within 7 days, and the frequency of acute brain infarction on DWI was significantly lower in the nonfocal group (focal, 24.1%; nonfocal, 7.2%; mixed, 22.2%; P < .01). There was no significant difference in the one-year event-free survival rates across the groups. Significantly higher stroke risk was observed in patients with one or more high-risk categories or the ABCD2 score (≥ 4) in the focal group (P = .021 and .26, respectively), whereas no significant difference was observed in the other groups. Across all symptom groups, significantly higher stroke risk was observed in patients showing acute infarcts on DWI evaluated within 7 days. CONCLUSIONS: Both high-risk categorization (≥ 1 potential high-risk factors) and ABCD2 score (≥ 4) alone were useful tools for identifying higher stroke risk in patients with focal symptom but not with nonfocal symptoms in isolation. Further studies are warranted in triage methods for TIA with nonfocal in isolation in conjunction with DWI.

A multicenter propensity score analysis of FOLFIRINOX vs gemcitabine plus nab-paclitaxel administered to patients with metastatic pancreatic cancer: results from the NAPOLEON study.

PURPOSE: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX, FFX) and gemcitabine plus nab-paclitaxel (GnP) are considered standard treatments for patients with metastatic pancreatic cancer. Direct comparisons are not available that establish which is optimal. METHODS: We conducted a propensity score-adjusted analysis of patients with metastatic pancreatic cancer to identify the therapeutic advantages of these standard therapies. We used clinical data as part of a multicenter retrospective study of patients with unresectable or recurrent pancreatic cancer treated with FFX or GnP (NAPOLEON study). RESULTS: FFX and GnP were initially administered to 102 and 153 patients, respectively. The GnP group comprised more patients of advanced age, worse performance status, lower body mass index, recurrence, and lower albumin concentrations. Median overall survival (OS) and progression-free survival (PFS) were 11.5 months and 5.8 months in the FFX group and 11.1 months and 5.9 months in the GnP group, respectively. Propensity score-adjusted analysis indicated that the administration of FFX or GnP was not independently associated with OS (adjusted hazard ratio [HR] 1.06; 95% confidence interval [CI] 0.76-1.47; P = 0.73). Similarly, the difference in PFS was not significant between groups (adjusted HR 0.93; 95% CI 0.68-1.26; P = 0.62). Gastrointestinal disorders were more common in the FFX group, whereas the frequencies of hematological, nervous system, and skin disorders were higher in the GnP group. CONCLUSION: The efficacies of FFX and GnP were comparable, although safety profiles differed and should be considered in selecting treatment.

Pancreatic neuroendocrine carcinoma G3 may be heterogeneous and could be classified into two distinct groups.

BACKGROUND/OBJECTIVES: Pancreatic neuroendocrine carcinoma (PanNEC)-G3 often presents along with genetic abnormalities such as KRAS, RB1, and TP53 mutations. However, the association between these genetic findings and response to chemotherapy and prognosis has not been clarified. This study aimed to clarify the clinicopathological features of PanNEC-G3. METHODS: We performed a subgroup analysis of the Japanese PanNEN-G3 study (multicenter, retrospective study), which revealed that Rb loss and KRAS mutation were predictors of the response to platinum-based regimen in PanNEN-G3. We re-classified WHO grades of PanNENs using the 2017 WHO classification and then analyzed the clinicopathological features and prognostic factors in 49 patients with PanNEC-G3. RESULTS: The rates of Rb loss and KRAS mutation in PanNEC-G3 were 54.5% and 48.7%, respectively. Patients with Rb loss and/or KRAS mutation showed a higher response rate to first-line platinum-based regimen than those without Rb loss or KRAS mutation (object response rate 70.0% vs 33.3%, odds ratio 9.22; 95% CI 1.26-67.3, P = 0.029), but tended to have shorter overall survival rates than those without Rb loss or KRAS mutation (median 239 vs 473 days, hazard ratio 2.11; 95% CI 0.92-4.86, P = 0.077). CONCLUSIONS: Patients with PanNEC-G3 have varied clinical outcomes for platinum-based regimen. When grouped based on Rb loss and KRAS mutation, there seemed to be two groups with distinct prognoses and responses to the platinum-based regimen. PanNEC-G3 could, therefore, be classified into two distinct groups based on immunohistochemical and genetic findings.

Surgery for Pancreatic Neuroendocrine Tumor G3 and Carcinoma G3 Should be Considered Separately.

BACKGROUND: The role of surgery in pancreatic neuroendocrine neoplasm grade 3 (pNEN-G3) treatment remains unclear. We aimed to clarify the role of surgery for pNEN-G3, which has recently been reclassified as pancreatic neuroendocrine tumor-G3 (pNET-G3) and pancreatic neuroendocrine carcinoma-G3 (pNEC-G3), with and without metastases, respectively. METHODS: We analyzed a subgroup of patients from the Japanese pancreatic NEC study, a Japanese multicenter case-series study of pNEN-G3. Pathologists subclassified 67 patients as having pNET-G3 or pNEC-G3 based on morphological features. We compared the overall survival (OS) rates among patients who were grouped according to whether they had undergone tumor-targeted surgery for tumors without (SwoM) or with (SwM) metastases, or non-surgical procedures (NS). RESULTS: Data from 21 patients with pNET-G3 (SwoM, n = 6; SwM, n = 5; NS, n = 10) and 46 patients with pNEC-G3 (SwoM, n = 8; SwM, n = 5; NS, n = 33) were analyzed. OS of patients with pNET-G3 was significantly longer after SwoM and SwM than with NS (p = 0.018 and p = 0.022). In contrast, OS did not significantly differ between either SwoM or SwM and NS (p = 0.093 and p = 0.489) among patients with pNEC-G3. CONCLUSION: The role of surgery should be considered separately for pNET-G3 and pNEC-G3. Although SwoM and SwM can be considered for pNET-G3, caution is advised before considering SwM and SwoM for pNEC-G3.

The utility of apoptosis inhibitor of macrophages as a possible diagnostic marker in patients with Crohn's disease.

BACKGROUND: Apoptosis inhibitor of macrophages (AIM) was initially identified as an apoptosis inhibitor that supports the survival of macrophages against various apoptosis-inducing stimuli, and AIM produced by macrophages may contribute to the pathogenesis of inflammatory bowel diseases (IBDs). However, there have been no reports on the kinetics of AIM in IBD and the impact of AIM on the pathogenesis of IBD. In this study, we aimed to investigate the diagnostic utility of levels of AIM and their correlation with the activity of Crohn's disease (CD) and IBD. METHODS: We used an enzyme-linked immunosorbent assay (ELISA) to examine AIM serum levels in 16 healthy subjects and 90 patients with inflammatory bowel diseases, namely 39 with CD and 51 with ulcerative colitis (UC), as well as 17 patients with Behcet's disease (BD) as intestinal disease controls. We compared serum AIM levels among groups and examined whether there were correlations between serum AIM levels and disease activity and type. We also performed immunohistochemical staining of AIM in intestinal tissues of patients with CD. RESULTS: Serum AIM levels were significantly higher in patients with CD than in patients with UC, BD, and controls (3.27 ± 2.14, 1.88 ± 1.43, 2.34 ± 1.37, and 2.13 ± 0.64 µg/ml, respectively; P < 0.01). There was no difference in serum AIM levels before and after treatment in patients with CD. However, in these patients the diagnostic rate using AIM was better than that based on anti-Saccharomyces cerevisiae antibodies. AIM was expressed in macrophages that were positive for CD14, CD16, or both in the intestinal tissues of patients with CD. CONCLUSIONS: AIM is a novel biomarker of CD that can distinguish CD from UC or BD. It is suggested that AIM may contribute to intestinal inflammation by inhibiting the apoptosis of macrophages.

Clinical impact of non-culprit lesions on 1-year mortality in very elderly patients with acute coronary syndrome.

Preventive percutaneous coronary intervention (PCI) for non-culprit lesions after primary PCI remains controversial in patients with acute coronary syndrome (ACS). We analyzed whether PCI for non-culprit lesions would be associated with a better long-term prognosis in very elderly (≥85 years) patients. This study included 91 consecutive patients with ACS (mean age, 88.2 ± 3.0, 52 % male). We investigated the association of residual lesions with 1-year mortality. Culprit lesions affected the left anterior descending artery (LAD) in 50 patients, the left circumflex artery (LCx) in 29, and the right coronary artery (RCA) in 31. Residual lesions affected LAD in 20 cases, LCx in 22, and RCA in 21 patients. Residual lesions in LAD were associated with a higher 1-year mortality (p = 0.013), whereas residual lesions in LCx or RCA were not (p = 0.547 and 0.473, respectively). A Cox regression model demonstrated that patients with residual lesions in LAD had an increased risk of 1-year mortality compared with those without residual lesions (hazard ratio, 2.39; 95 % confidence interval, 1.16-4.96; p = 0.019). Therefore, the option to not treat residual lesions in LAD of patients with PCI may be associated with a higher 1-year mortality. Further studies are needed to confirm these findings.

Diagnostic efficacy of liquid-based cytology for solid pancreatic lesion samples obtained with endoscopic ultrasound-guided fine-needle aspiration: Propensity score-matched analysis.

BACKGROUND AND AIM: There is a paucity of data on the diagnostic efficacy of liquid-based cytology (LBC) for pancreatic samples obtained by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). Using propensity score matching, we retrospectively analyzed the additional diagnostic value of LBC compared to a conventional Papanicolaou smear (CPS) for samples of solid pancreatic lesions obtained by EUS-FNA. METHODS: This cohort study included 126 matched patients who underwent initial EUS-FNA for solid pancreatic lesions between January 2009 and August 2014. CPS was used for cytology of EUS-FNA samples obtained until May 2012 (63 patients). Subsequently, LBC was used for cytological analysis (63 patients). Diagnostic yields of CPS and LBC for malignancy were compared. Risk factors for cytological misdiagnosis with LBC were investigated. RESULTS: Overall rate of malignancy was 86% after matching. LBC had higher diagnostic sensitivity and accuracy than CPS (96.6% vs 84.0%, P = 0.03; and 96.8% vs 87.3%, P = 0.05). LBC was significantly more sensitive for diagnosing pancreatic head lesions (96.4% vs 78.1%, P = 0.04). The sensitivity for pancreatic ductal adenocarcinoma (PDAC) with LBC was higher (98.1% vs 83.0%, P = 0.009). Multivariate analysis revealed that malignant tumors other than PDAC (P = 0.004) and lesion size ≤20 mm (P = 0.046) were risk factors for LBC misdiagnosis in all participants. CONCLUSIONS: For solid pancreatic lesions, LBC of EUS-FNA samples contributes to the diagnosis of malignancy. Malignant tumors other than PDAC and small tumors are difficult to diagnose using EUS-FNA and LBC.

Fecal Human Neutrophil Peptide Levels Correlate with Intestinal Inflammation in Ulcerative Colitis.

BACKGROUND/AIM: Fecal markers have recently been found to provide convenient and noninvasive assessment of intestinal inflammation in inflammatory bowel disease (IBD). In this study, we examined the clinical significance of fecal human neutrophil peptides (F-HNP) in the evaluation of IBD disease activity. METHODS: This study enrolled 70 patients with IBD, consisting of 45 patients with ulcerative colitis (UC), 25 patients with Crohn's disease (CD), and 11 non-IBD controls. Stools samples were evaluated for the association between F-HNP concentration and disease and endoscopic activity in each group and the correlation between F-HNP and fecal calprotectin (F-CP) concentrations. RESULTS: Median F-HNP levels were as follows: UC: 25.6 ng/ml; CD: 20.1 ng/ml; and non-IBD controls: 4.9 ng/ml. F-HNP levels were significantly higher in each IBD group, especially in the UC group, than in the control group. In the UC group, both F-HNP and F-CP levels were significantly higher during active disease compared to the remission phase. Both markers were significantly correlated with the Mayo endoscopic score, although the correlation was stronger for F-HNP than for F-CP (r = 0.66 vs. r = 0.54). CONCLUSION: F-HNP is a noninvasive marker that is useful for evaluating UC endoscopic activity.

Implementation of a Community-Based Triage for Patients with Suspected Transient Ischemic Attack or Minor Stroke Study: A Prospective Multicenter Observational Study.

BACKGROUND: Japan has the highest number of magnetic resonance imaging units in the world, and citizens can freely choose medical care at any hospital or clinic. We aimed to investigate the triage of patients with suspected transient ischemic attack (TIA) or minor stroke in this unique Japanese healthcare system. METHODS: In this cohort study, patients with suspected TIA or minor stroke (National Institutes of Health Stroke Scale score <4) within 7 days after onset were prospectively enrolled and followed for 1 year. The high-risk group was defined as having at least one of the following 5 items at the initial visit: (1) atrial fibrillation, (2) carotid stenosis, (3) crescendo TIA, (4) definite focal brain symptoms, or (5) ABCD2 score of 4 or higher. After the initial assessment, the patients were diagnosed as having acute ischemic cerebrovascular syndrome (AICS) or stroke mimic. AICS was classified into 3 categories including definite, probable, and possible AICS, based on evidence of neurological deficits and brain infarction on the imaging study. RESULTS: A total of 353 patients were enrolled and 89.8% of the patients were examined by diffusion-weighted imaging at the initial visit. Kaplan-Meier analyses demonstrated a statistically significant difference in subsequent stroke risk when the patients were triaged by the ABCD2 score (P = .031), 5-item high-risk categorization (P = .032), or AICS classification (P = .001). CONCLUSIONS: This study demonstrates that hospitals and clinics with imaging facilities play a major role in triage and that the ABCD2 score, 5-item high-risk categorization, and AICS classification are useful as triage tools for patients with suspected TIA or minor stroke.

Ferroptosis is involved in cisplatin sensitivity of the S3 segment of immortalized proximal tubule cells.

Cisplatin (CDDP) is administered as an anticancer drug across a broad spectrum of cancer treatments, but it causes severe renal damage. Several studies have attempted to elucidate the cause of CDDP-induced renal injury, but the detailed mechanism remains unclear. We previously found that S3 cells are more sensitive to CDDP than S1 and S2 cells by using immortalized cells derived from S1, S2, and S3 segments of proximal tubules. In this study, we investigated the potential contribution of reactive oxygen species (ROS) to the sensitivity of S3 cells to CDDP. The results showed that S3 cells have high sensitivity to CDDP, paraquat (PQ) and three ROS substances. To examine the mechanisms underlying the sensitivity to ROS in S3 cells, we compared the cellular responses of CDDP- and PQ-exposed S3 cells. The results indicated that the levels of intracellular ROS and lipid peroxides were increased in S3 cells after CDDP and PQ exposure. The intracellular levels of antioxidant proteins such as thioredoxin, thioredoxin reductase 1 and glutathione peroxidase 4 were also increased by exposure to PQ, but these proteins were decreased by CDDP exposure in S3 cells. Furthermore, the levels of intracellular free Fe2+ were increased by CDDP exposure only in S3 cells but not S1 or S2 cells, and cytotoxicity by exposure to CDDP in S3 cells was suppressed by ferroptosis inhibitors. These results suggested that the induction of ferroptosis due to the ROS production through attenuation of the antioxidant system and elevated free Fe2+ is partly responsible for the sensitivity of S3 cells to CDDP.

A multicenter retrospective observational NAPOLEON2 study of nanoliposomal irinotecan with fluorouracil and folinic acid in patients with unresectable pancreatic cancer.

Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen after gemcitabine-based therapy for patients with unresectable or recurrent pancreatic cancer. However, there are limited clinical data on its efficacy and safety in the real-world. We therefore initiated a retrospective and prospective observational study (NAPOLEON-2). The results of the retrospective part were reported herein. In this retrospective study, we evaluated 161 consecutive patients who received NFF as second-or-later-line regimen. The main endpoint was overall survival (OS), and the other endpoints were response rate, disease control rate, progression-free survival (PFS), dose intensity, and adverse events (AEs). The median age was 67 years (range, 38-85 years). The median OS and PFS were 8.1 and 3.4 months, respectively. The objective response and disease control rates were 5% and 52%, respectively. The median relative dose intensity was 81.6% for nanoliposomal irinotecan and 82.9% for fluorouracil. Grade 3 or 4 hematological and nonhematological AEs occurred in 47 and 42 patients, respectively. Common grade 3 or 4 AEs included neutropenia (24%), anorexia (12%), and leukocytopenia (12%). Subanalysis of patients treated with second-line and third-or-later-line demonstrated no statistical significant difference in OS (7.6 months vs. 9.1 months, respectively; hazard ratio, 0.92; 95% confidence interval, 0.64-1.35; p = 0.68). In conclusion, NFF has acceptable efficacy and safety profile even in real-world clinical settings. The prospective study is in progress to validate these findings.

CHAC1 exacerbates arsenite cytotoxicity by lowering intracellular glutathione levels.

We here examined whether CHAC1 is implicated in arsenite (As(III))-induced cytotoxicity in HaCaT cells. We found that HaCaT cells in which the intracellular GSH levels were elevated by transfection with CHAC1 siRNA showed decreased sensitivity to As(III) compared to the control cells. Treatment with BSO (an inhibitor of GSH biosynthesis) abolished the decrease in sensitivity to As(III), suggesting that an increase in intracellular GSH levels was involved in the decrease in sensitivity to As(III) due to the decrease in the levels of CHAC1 expression. When we examined the expression of CHAC1 after exposure of HaCaT cells to As(III), the levels of CHAC1 were increased. Since CHAC1 is a proapoptotic factor, we examined appearance of apoptotic cells and cleavage of caspase-3 after exposure to As(III) to determine whether As(III)-induced CHAC1 up-regulation was involved in apoptosis induction. The results showed that induction of apoptosis by As(III) exposure was not detected in CHAC1 siRNA-transfected cells. Together, our findings indicate that CHAC1 is involved in the sensitivity of HaCaT cells to As(III) by regulating the intracellular GSH levels, and in particular, CHAC1 is involved in As(III)-induced apoptosis.

Effects of methylation of arginine residue 83 on the enzymatic activity of human arsenic (+3 oxidation state) methyltransferase.

Arsenic (+3 oxidation state) methyltransferase is an enzyme responsible for arsenic methylation, and it requires S-adenosyl-methionine (SAM) as a coenzyme. We here generated two mutants to clarify the role of the highly conserved 83rd arginine residue (Arg83) in Motif I, the SAM-binding domain, of human AS3MT. When the AS3MT activity was compared between the mutants and the wild type (WT) recombinant protein, little activity was detected in the glycine mutant (Arg83Gly) or lysine mutant (Arg83Lys). When we examined the ability of transfected HEK293 cells exposed to arsenite to methylate arsenic, the methylation ability was significantly reduced in Arg83Gly compared to the WT, but was not significantly different between Arg83Lys and WT. Western blot analysis of the recombinant WT and Arg83Gly with an antibody that recognizes methylated Arg showed that an Arg residue in the WT was mono- and di-methylated, but not in Arg83Gly. Furthermore, a peptide containing dimethylated Arg83 was detected by MALDI-TOF/MS of the WT digested with chymotrypsin. These results indicate that AS3MT maintains its enzymatic activity through the methyl modification of Arg83.

Comprehensive evaluations of a prototype full field-of-view photon counting CT system through phantom studies.

Objective. Photon counting CT (PCCT) has been a research focus in the last two decades. Recent studies and advancements have demonstrated that systems using semiconductor-based photon counting detectors (PCDs) have the potential to provide better contrast, noise and spatial resolution performance compared to conventional scintillator-based systems. With multi-energy threshold detection, PCD can simultaneously provide the photon energy measurement and enable material decomposition for spectral imaging. In this work, we report a performance evaluation of our first CdZnTe-based prototype full-size PCCT system through various phantom imaging studies.Approach.This prototype system supports a 500 mm scan field-of-view and 10 mmz-coverage at isocenter. Phantom scans were acquired using 120 kVp from 50 to 400 mAs to assess the imaging performance on: CT number accuracy, uniformity, noise, spatial resolution, material differentiation and quantification.Main results.Both qualitative and quantitative evaluations show that PCCT, under the tested conditions, has superior imaging performance with lower noise and improved spatial resolution compared to conventional energy integrating detector (EID)-CT. Using projection domain material decomposition approach with multiple energy bin measurements, PCCT virtual monoenergetic images have lower noise, and good accuracy in quantifying iodine and calcium concentrations. These results lead to increased contrast-to-noise ratio (CNR) for both high and low contrast study objects compared to EID-CT at matched dose and spatial resolution. PCCT can also generate super-high resolution images using much smaller detector pixel size than EID-CT and greatly improve image spatial resolution.Significance.Improved spatial resolution and quantification accuracy with reduced image noise of the PCCT images can potentially lead to better diagnosis at reduced radiation dose compared to conventional EID-CT. Increased CNR achieved by PCCT suggests potential reduction in iodine contrast media load, resulting in better patient safety and reduced cost.

Comparison of recurrent biliary obstruction with the use of metal and plastic stents in EUS-guided biliary drainage: A propensity score-matched analysis.

Background and Objectives: In transpapillary biliary drainage, metal stents (MSs) exhibit a lower incidence of a biliary obstruction than plastic stents (PSs). However, few studies have compared recurrent biliary obstruction (RBO) when MSs and PSs are used in EUS-guided hepaticogastrostomy (EUS-HGS) and choledochoduodenostomy (EUS-CDS). We retrospectively evaluated the RBO for both stents in each procedure. Patients and Methods: : Between November 2012 and December 2020, 85 and 53 patients who underwent EUS-HGS and EUS-CDS for unresectable malignant biliary obstruction, respectively, were enrolled. Factors associated with RBO were assessed. Clinical outcomes were compared between the MS and PS groups using propensity score matching. Results: : The clinical success rate and procedure-related adverse events were similar in the MS and PS groups. Multivariate analysis identified the use of PS as a factor associated with RBO (EUS-HGS, P = 0.03; EUS-CDS, P = 0.02). After matching, the median time to RBO in EUS-HGS (MS: 313; PS: 125 days; P = 0.01) in the MS group was longer than that in the PS group. The cumulative incidence of RBO at 1, 3, and 6 months in the MS group was significantly lower than that in the PS group for EUS-HGS (MS: 4.0%, 8.2%, and 8.2%; PS: 12.4%, 24.9%, and 39.5%, respectively, P = 0.01). Conclusions: : MS exhibited a lower rate of RBO than PS for EUS-HGS and EUS-CDS.