CALN1 hypomethylation as a biomarker for high-risk bladder cancer.

BACKGROUND: DNA methylation in cancer is considered a diagnostic and predictive biomarker. We investigated the usefulness of the methylation status of CALN1 as a biomarker for bladder cancer using methylation-sensitive restriction enzyme (MSRE)-quantitative polymerase chain reaction (qPCR). METHODS: Eighty-two bladder cancer fresh samples were collected via transurethral resection of bladder tumors. Genomic DNA was extracted from the samples, and MSRE-qPCR was performed to determine the CALN1 methylation percentage. Reverse transcription-qPCR was performed to assess the correlation between CALN1 methylation and mRNA expression. The association between CALN1 methylation percentage and clinicopathological variables of all cases and intravesical recurrence of non-muscle-invasive bladder cancer (non-MIBC) cases were analyzed. RESULTS: Of the 82 patients, nine had MIBC and 71 had non-MIBC who had not undergone total cystectomy. The median CALN1 methylation percentage was 79.5% (interquartile range: 51.1-92.6%). The CALN1 methylation percentage had a negative relationship with CALN1 mRNA expression (Spearman's ρ = - 0.563 and P = 0.012). Hypomethylation of CALN1 was associated with advanced tumor stage (P = 0.0007) and histologically high grade (P = 0.018). Furthermore, multivariate analysis revealed that CALN1 hypomethylation was an independent risk factor for intravesical recurrence in non-MIBC patients (hazard ratio 3.83, 95% confidence interval; 1.14-13.0, P = 0.031). CONCLUSION: Our findings suggest that CALN1 methylation percentage could be a useful molecular biomarker for bladder cancer.

Predictive factors of rectal hemorrhage in patients with localized prostate cancer who underwent low-dose-rate brachytherapy.

BACKGROUND: This study aimed to evaluate the association between clinical covariates or the prescribed radiation dose for the prostate and rectal hemorrhage in patients with prostate cancer (PCa) who received iodine-125 low-dose-rate brachytherapy (LDR-BT group) or the combination of LDR-BT and external beam radiation therapy (CMT group). METHODS AND MATERIALS: In this retrospective study, we reviewed the clinical records of 298 consecutive PCa patients with clinical stage T1c/T2 who underwent LDR-BT between August 2004 and August 2016 at a single institution. The prescribed minimum peripheral doses were 145 Gy for the LDR-BT group and 104 Gy for the CMT group. The dosimetric parameters analyzed were minimal dose received by 90% of the prostate gland, biologically effective dose, and rectal volume receiving 100% (RV100) or 150% of the prescribed dose. The endpoint of this study was the onset of any-grade clinical rectal hemorrhage after treatment. RESULTS: The median follow-up period was 6.8 years. The 5-year overall survival rate was found to be 98.3%, and two patients (0.7%) reported biochemical recurrence during follow-up period. A total of 33 patients (11%) experienced rectal hemorrhage. However, ≥ grade 2 rectal hemorrhage occurred in eight patients (2.7%). On multivariate analysis, CMT, RV100 ≥ 0.66 mL, and hemorrhoids before treatment were identified as predictors of rectal hemorrhage after radiation therapy. CONCLUSIONS: Maximal reduction of the rectal dose seems very important to prevent serious rectal hemorrhage. In addition, we should consider the risk of rectal toxicities in patients with abnormalities in the rectal mucosa, especially hemorrhoids.

The Utility and Efficacy of Laparoscopic Radical Cystectomy in Patients with Muscle-Invasive Bladder Cancer at a Single Institution.

BACKGROUND: The aim of this study was to compare the surgical and oncological outcomes and complications of laparoscopic radical cystectomy (LRC) to those of open radical cystectomy (ORC) in patients with muscle-invasive bladder cancer (MIBC). METHODS: Our study focused on patients with histologically confirmed stage T2-T4a urothelial carcinoma of the bladder without distant metastases, who underwent LRC (LRC group) or ORC (ORC group). The primary endpoints in this study were the overall survival (OS) and recurrence-free survival (RFS) rates. RESULTS: In this study, 59 patients, 17 underwent LRC and 42 underwent ORC, were enrolled. The 2-year OS rate was 100% in the LRC group and 88.0% in the ORC group (p = 0.85). The 2-year RFS rate was 63.5% in the LRC group and 69.5% in the ORC group (p = 0.321). On multivariate analysis, the histological type, positive lymph node, and positive resection margin were significantly associated with the OS rates. CONCLUSIONS: This study suggested that LRC may achieve similar oncological outcomes and fewer perioperative complications and less blood loss compared to ORC. Therefore, LRC should be considered as one of the treatment options for patients with MIBC.

New method for determining fibrinogen and FDP threshold criteria by artificial intelligence in cases of massive hemorrhage during delivery.

AIM: To investigate the feasibility of a novel method using artificial intelligence (AI), in which the fibrinogen criterion was determined by the quantitative relation between the distributions of fibrin/fibrinogen degradation products (FDPs) and fibrinogen. METHODS: A dataset of 154 deliveries comprising more than 2000 g of blood lost due to hemorrhage, excluding disseminated intravascular coagulation (DIC), among patients from eight national perinatal centers in Japan from 2011 to 2015 were obtained. The fibrinogen threshold criterion was identified by using the function that best fit the distributions of FDP as determined by AI. FDP production was described by differential equations using a dataset containing fibrinogen levels less than the fibrinogen criterion and solved numerically. RESULTS: A fibrinogen level of 237 mg/dL as the threshold criterion was obtained. The FDP threshold criteria were 2.0 and 8.5 mg/dL for no coagulopathy and a failed coagulation system, respectively. CONCLUSION: The fibrinogen threshold criterion for patients with massive hemorrhage excluding DIC at delivery were obtained by selecting the functions that best fit the distributions of FDP data by using AI.

Comparison of single- and multiple-dose cefazolin as prophylaxis for transurethral enucleation of prostate: A multicenter, prospective, randomized controlled trial by the Japanese Research Group for Urinary Tract Infection.

OBJECTIVES: To compare the optimal administration period of antimicrobial prophylaxis in patients undergoing transurethral enucleation of the prostate for benign prostatic hyperplasia. METHODS: We carried out a randomized controlled trial to compare the differences in incidence of perioperative genitourinary tract infection between single and multiple (3 days) administrations of cefazolin for transurethral enucleation of the prostate in benign prostatic hyperplasia patients without pyuria or bacteriuria between January 2015 and December 2018. RESULTS: This multicenter randomized controlled trial included 203 patients who underwent a transurethral enucleation of the prostate procedure. All received antimicrobial prophylaxis, and were randomized into those who received single-dose (n = 101) or multiple-dose (n = 102) therapy. The rate of genitourinary tract infection after transurethral enucleation of the prostate for all patients was 1.5%, whereas that in the single-dose group was 1.0% and in the multiple-dose group was 2.0%, which were not significantly different (P = 1.00). CONCLUSIONS: A single dose of antimicrobial prophylaxis as a prophylactic antibacterial drug is sufficient for patients undergoing transurethral enucleation of the prostate who do not have presurgical pyuria or bacteriuria.

[Retroperitoneal Dedifferentiated Liposarcoma which Could Be Diagnosed Using Dual Color in Situ Hybridization : A Case Report].

Ten years ago, a seventy-year-old female underwent extirpation of a left retroperitoneal tumor that was 58×36 mm in size. The pathological diagnosis was malignant peripheral nerve sheath tumor (MPNST) at that time. The patients visited our hospital with the chief complaint of back pain at ten years after surgery. Computer tomography (CT) showed recurrent tumors at the pancreas and the left kidney. Fine-needle aspiration biopsy was performed because of the possibility of pancreatic tumor. The pathological diagnosis was the recurrence of MPNST. The patient underwent extirpation of the recurrent tumors along with the pancreatic body and tail, transverse colon, spleen and left kidney. The definitive diagnosis was dedifferentiated liposarcoma with murine double minute 2 (MDM2) gene amplification and positive of p16Ink4 (p16). The previously resected tumor also revealed MDM2 gene amplification and positive of p16. Based on these results, our diagnosis in this case was recurrence of dedifferentiated liposarcoma. At 6 months after surgery, the patient had no local recurrence or distant metastases.

[Metachronous Pubic Bone Metastases from Synchronous Double Cancer with Prostate and Ascending Colon Cancers : A Case Report].

A 70-year-old man visited a private hospital with the chief complaint of right lower limb pain. Fluorodeoxyglucose-emission tomography (FDG-PET) showed abnormal uptake in the pubic bone, right femur, and ascending colon. The patient was referred to our hospital for further evaluation. The following tumor marker levels were found : prostate-specific antigen (PSA) 20.57 ng/ml, carcinoembryonic antigen (CEA) 108.5 ng/ml, carbohydrate antigen 19-9 (CA19-9) 1,002.1 U/ml. An open pubic bone biopsy was performed. The pathological diagnosis was metastatic adenocarcinoma from prostate cancer. Prostate and ascending colon cancers were clinically diagnosed as T2bN0M1b and T2N0M0, respectively. Laparoscopic colectomy was performed. Androgen deprivation therapy started immediately and the serum PSA level was maintained at <0.2 ng/ml during the follow-up period. However, the CEA and CA19-9 were higher than the normal level 2 years after the surgery. In addition, the FDG-PET revealed abnormal uptake in the pubic bone. Thus, a pubic bone biopsy was performed again. The histological diagnosis was metastatic adenocarcinoma from the ascending colon cancer. Although the patient received combination chemotherapy, he died of colon cancer.

High-intensity breastfeeding improves insulin sensitivity during early post-partum period in obese women with gestational diabetes.

AIM: To investigate whether high-intensity breastfeeding (HIB) reduces insulin resistance during early post-partum period in women with gestational diabetes (GDM), independent of post-partum weight change (PWC). MATERIALS AND METHODS: In this multicentre prospective study, we included Japanese women with GDM who underwent a 75-g oral glucose tolerance test (OGTT) during early post-partum. We measured plasma insulin during OGTT to obtain a homeostasis model of assessment of insulin resistance (HOMA-IR). We defined the condition in which infants were fed by breastfeeding alone or greater than or equal to 80% of the volume as HIB, and other statuses, including partial and nonbreastfeeding, as non-HIB. We investigated the association between post-partum HOMA-IR and the breastfeeding status after adjusting for confounders including PWC. RESULTS: Among 222 women with GDM who underwent the OGTT at 7.9 ± 2.3 weeks post-partum with a PWC of -7.8 ± 3.4 kg, although the rate of abnormal glucose tolerance (prediabetes and diabetes) did not differ between the groups (33% vs 32%), the HOMA-IR in the HIB women (n = 166) was significantly lower than that in the non-HIB women (n = 56) (1.12 ± 0.85 vs 1.72 ± 1.43, P = 0.0002). The effect of the HIB was independently associated with lower HOMA-IR after adjusting for confounders including PMC. However, the subgroup analysis according to their pre-pregnancy obesity states showed that the effect was seen only in the obese subjects (BMI ≥ 25). CONCLUSIONS: In obese Japanese women with GDM, HIB has a significant effect in reducing insulin resistance during early post-partum, independent of the post-partum weight loss.

Risk factors and incidence of malignant neoplasms after kidney transplantation at a single institution in Japan.

BACKGROUND: The risk of malignant neoplasms increases in kidney transplantation (KT) recipients (KTRs). However, Japanese registry studies have not been reported since 2000. METHODS: We retrospectively reviewed the medical records of 346 patients who underwent KT at Gifu University Hospital, Japan since 2000. Patients were divided into two groups based on whether they developed malignancy after KT or not. The incidence, type of malignancy, risk factors, and prognosis for malignancy were examined. RESULTS: In this study, 22 de novo malignant neoplasms were identified in 20 KTRs (7.3%), with a median follow-up period of 8.2 years. Cumulative incidence of any malignant neoplasms was 1.1% within 1 year and 4.4% within 5 years. The 5-year overall survival (OS) rates were 71.8% in KTRs with malignant neoplasms and 98.6% in KTRs without malignant neoplasms. Uni- and multivariate analysis revealed that age at KT and acute rejection (AR) episode were significant predictors for incidence of malignancy. CONCLUSIONS: The development of malignant neoplasms was associated with poor OS and graft survival. We consider that appropriate screening and investigation of symptoms are important for KTRs, particularly for older KTRs at transplantation and those with AR episode.

The resonance® metallic ureteral stent in the treatment of malignant ureteral obstruction: a prospective observational study.

BACKGROUND: To study the outcomes and experiences of using metallic stents in treating patients with malignant ureteral obstruction (MUO), we examined the effects of metallic ureteral stenting using the Cook Resonance® stent in the treatment of MUO. METHODS: All patients who had a Resonance metallic stent inserted between April 2015 and March 2018 at one of multiple facilities were prospectively observed with a 1-year follow-up. The primary outcome was the patency rate of the metallic ureteral stent. The secondary outcomes included the complications (e.g., infection and fever). RESULTS: Although stent insertion was attempted in 50 patients, the stent could not be inserted as a ureteral stent in three patients due to severe ureteral stricture, and one ureteral cancer patient was excluded from the analysis. The remaining 46 patients' median age was 67 years (range 28-85 years) (16 males, 30 females). Twenty-four patients died during the study; their median survival time was 226 days. The median follow-up period for the censored patients was 355 days (range 16-372 days), and just seven patients were still alive without Resonance failure > 1 year later. The women's IPSS scores tended to be lower than those of the men. Regarding the OABSS score, although the women's total score tended to be low, the difference between the men's and women's scores was nonsignificant. The bacteria detected from urine culture after stent insertion were more gram-positive than gram-negative. CONCLUSION: Metallic ureteric stenting using the Resonance stent is safe and effective for treating MUO. Subjective symptoms were relatively less in the female patients.

[Cardiac Metastasis in a Patient with Clear Cell Renal Cell Carcinoma who Underwent Multimodality Therapy for Multiple Metastases after Radical Nephrectomy].

The patient underwent laparoscopic left radical nephrectomy for clear cell renal cell carcinoma (ccRCC). After surgery, the patient had multiple lung metastases and underwent the combination therapy of radiofrequency ablation, interferon-alpha, and inteleukin-2. Thereafter, computed tomography showed multiple lymph node and brain metastases. The patient was administered targeted therapy and radiation. Eventually, the patient suddenly complained of dyspnea. An echocardiogram, coronary angiography and magnetic resonance imaging suggested acute heart failure and pericardial effusion due to a metastatic tumor in the cardiac anteroseptal and posterior wall. Nivolumab was administered for cardiac metastases. The patient has been in stable condition with no progression of cardiac metastases after the administration of nivolumab for 22 months.

The egg membrane microdomain-associated uroplakin III-Src system becomes functional during oocyte maturation and is required for bidirectional gamete signaling at fertilization in Xenopus laevis.

In Xenopus laevis, sperm-egg interaction promotes partial proteolysis and/or tyrosine phosphorylation of uroplakin III (UPIII) and the tyrosine kinase Src, which both localize to the cholesterol-enriched egg membrane microdomains (MDs). Here we show that sperm promote proteolysis and/or tyrosine phosphorylation of UPIII and Src in MDs isolated from ovulated and unfertilized eggs (UF-MDs). An antibody against the extracellular domain of UPIII interferes with these events. Inhibition of fertilization by anti-UPIII antibody is rescued by co-incubation with UF-MDs. This suggests that, like MDs in intact eggs, the isolated UF-MDs are capable of interacting with sperm, an interaction that does not interfere with normal fertilization but rather augments the ability of sperm to fertilize eggs pretreated with anti-UPIII antibody. This unexpected effect of UF-MDs on sperm requires UPIII function in UF-MDs and protein kinase activity in sperm. MDs isolated from progesterone-treated mature oocytes, but not ovarian immature oocytes, are similarly functional as UF-MDs. The anti-UPIII extracellular domain antibody binds more effectively to the surface of mature than immature ovarian oocytes. We propose that the structural and functional competency of the UPIII-Src signaling system in MDs is strictly regulated during oocyte maturation and subsequently in sperm-mediated egg activation and fertilization. The fertilization-related signaling properties seen in UF-MDs can be partially reconstituted in MDs of human embryonic kidney 293 cells (293-MDs) expressing UPIII, Src and uroplakin Ib. However, 293-MDs expressing a proteolysis-resistant mutant of UPIII are less functional, suggesting that the availability of UPIII to protease action is important for MD function.

Retrospective study of tadalafil for fetal growth restriction: Impact on maternal and perinatal outcomes.

AIM: The aim of this retrospective study was to assess tadalafil treatment in pregnant women with fetal growth restriction (FGR) in terms of maternal and perinatal outcomes. METHODS: We retrospectively analyzed 11 Japanese singleton pregnant women with FGR who received tadalafil along with conventional management for FGR at Mie University Hospital from July 2015 to February 2016 (tadalafil group). These women were matched for maternal age, parity, gestational age, and estimated fetal weight at enrollment with 14 singleton pregnant women who received only the conventional management for FGR in 2014 (conventional management group). The conventional management for FGR was performed according to guidelines for obstetric practice in Japan. RESULTS: Both birthweight and fetal growth velocity from enrollment to birth were significantly higher in the tadalafil group than in the conventional management group. The cesarean delivery rate was approximately twofold higher in the conventional management group than in the tadalafil group. Importantly, cesarean section due to non-reassuring fetal status was performed in seven pregnant women in the conventional management group (58.3%) but in none in the tadalafil group (P < 0.05, chi-squared test). CONCLUSIONS: Tadalafil may improve perinatal outcome in FGR by modulating fetal growth through maintenance or improvement of fetal well-being.

[A Case of Adult Mature Teratoma Located in Retroperitoneum].

A 35-year-old man wasreferred to our hospital for treatment of a right adrenal tumor detected by ultrasonography during a physical check-up. Contrast-enhanced abdominal computed tomography revealed a poorly enhanced 74 mm tumor situated adjacent to the upper pole of the right kidney. The tumor consisted of fat with peripheral calcification. Magnetic resonance imaging also revealed a right retroperitoneal tumor with fatty contents and well-circumscribed capsule. The endocrine examination revealed the tumor as non-functioning. These findings were suggestive of a right adrenal myelolipoma. We performed laparoscopic right adrenalectomy because of its large size and malignant potency. The pathological examination revealed the retroperitoneal tumor asa mature teratoma existing apart from the adrenal gland. Primary retroperitoneal teratomasare relatively rare. Herein, we report thiscas e of adult mature teratoma occurring in the retroperitoneum.

Prognostic value of various nutritional risk markers in patients hospitalized for the treatment of genitourinary cancer: A retrospective study.

BACKGROUND & AIMS: Because malnutrition adversely affects the prognosis of patients with cancer, accurate nutritional status assessment is important. Therefore, this study aimed to verify the prognostic value of various nutritional assessment tools and compare their predictability. METHODS: We retrospectively enrolled 200 patients hospitalized for genitourinary cancer between April 2018 and December 2021. Four nutritional risk markers, namely, Subjective Global Assessment (SGA) score, Mini-Nutritional Assessment-Short Form (MNA-SF) score, Controlling Nutritional Status (CONUT) score, and Geriatric Nutritional Risk Index (GNRI), were measured at admission. The endpoint was all-cause mortality. RESULTS: SGA, MNA-SF, CONUT, and GNRI values were all independent predictors of all-cause mortality (hazard ratio [HR] = 7.72, 95% confidence interval [CI]: 1.75-34.1, P = 0.007; HR = 0.83, 95% CI: 0.75-0.93, P = 0.001; HR = 1.29, 95% CI: 1.16-1.43, P < 0.001; and HR = 0.95, 95% CI: 0.93-0.98, P < 0.001, respectively) even after adjustment for age, sex, cancer stage, and surgery or medication. However, in the model discrimination analysis, the net reclassification improvement of the CONUT model (vs. SGA: 0.420, P = 0.006 and vs. MNA-SF: 0.57, P < 0.001) and GNRI model (vs. SGA: 0.59, P < 0.001 and vs. MNA-SF: 0.671, P < 0.001) were significantly improved compared to the SGA and MNA-SF models, respectively. The combination of CONUT and GNRI models also had the highest predictability (C-index = 0.892). CONCLUSIONS: Objective nutritional assessment tools were superior to subjective nutritional tools in predicting all-cause mortality in inpatients with genitourinary cancer. Measurement of both the CONUT score and GNRI might contribute to a more accurate prediction.

Prognostic Value of the Controlling Nutritional Status (CONUT) Score in Patients at Dialysis Initiation.

Protein-energy wasting (PEW) is common in patients with chronic kidney disease (CKD), and affects their prognosis. The Controlling Nutritional Status (CONUT) score is a nutritional screening tool calculated using only blood test data. This study aimed to investigate the prognostic value of CONUT score in patients just initiating dialysis. A total of 311 CKD patients who stably initiated dialysis were enrolled. Only 27 (8.7%) patients were classified as having normal nutritional status. The CONUT score was also independently correlated with elevated C-reactive protein levels (ß = 0.485, p < 0.0001). During the median follow-up of 37 months, 100 patients (32.2%) died. The CONUT score was an independent predictor of all-cause mortality (adjusted hazard ratio 1.13, 95% confidence interval 1.04−1.22, p < 0.0024). As model discrimination, the addition of the CONUT score to a prediction model based on established risk factors significantly improved net reclassification improvement (0.285, p = 0.028) and integrated discrimination improvement (0.025, p = 0.023). The CONUT score might be a simplified surrogate marker of the PEW with clinical utility and could predict all-cause mortality, in addition to improving the predictability in CKD patients just initiating dialysis. The CONUT score also could predict infectious-disease mortality.

The utility of laparoscopic partial nephrectomy with renal function preservation, regardless of warm ischemia time, compared with laparoscopic radical nephrectomy.

INTRODUCTION: This study aimed to evaluate the chronologic changes in renal function after laparoscopic partial (LPN) or radical nephrectomy (LRN) in patients with clinical T1 renal cell carcinoma. METHODS: In this retrospective study, patients with clinical stage T1 renal cell carcinoma who underwent LPN or LRN were divided into three groups, namely, LPN-A group including LPN patients with WIT ≤25 minutes, LPN-B group including LPN patients with WIT >25 minutes, and LRN group. Perioperative complications that occurred within 30 days after surgery were retrieved. All patients were followed-up every 3 months to evaluate the estimated glomerular filtration rate. The primary endpoint of this study was to assess the chronological changes in renal function after surgery. RESULTS: A total of 153 patients were enrolled in this study. The change in estimated glomerular filtration rate between day 1 and 2 weeks after surgery was significantly lower in the LPN-B group than in the LPN-A group (p<0.005). Both LPN-A and -B groups achieved eGFR ≥90% 2 weeks after surgery. In addition, the estimated glomerular filtration rate decline from post-operative day 1 through 24 months in the LPN-A group or the LPN-B group was significantly smaller than that in the LRN group (P < 0.001, P < 0.001, respectively). CONCLUSION: Our results demonstrate the efficacy and safety of LPN in patients with T1 renal cell carcinoma. Although complication rates were similar in both groups, post-operative renal function was not different between the LPN-A and -B groups.

Profiling of Serum Extracellular Vesicles Reveals miRNA-4525 as a Potential Biomarker for Advanced Renal Cell Carcinoma.

AIM: To identify novel diagnostic markers for renal cell carcinoma (RCC), we analyzed miRNAs in serum extracellular vesicles (EVs). MATERIALS AND METHODS: EVs were purified from serum of healthy controls and patients with localized and advanced RCC using T-cell immunoglobulin domain and mucin domain-containing protein 4 conjugated to magnetic beads. miRNA profiling of EVs was conducted by microarray analysis. miRNA expression was examined by quantitative reverse transcription-polymerase chain reaction. Lastly, proteomic analysis of RCC cells transfected with a miRNA inhibitor was performed to identify its potential targets. RESULTS: Microarray analysis revealed that nine miRNAs were increased by more than 1.5-fold in EVs from patients with RCC. Among them, miRNA-4525 was significantly elevated; miRNA-4525 expression was higher in RCC tissue than in the adjacent normal tissue. Proteomic analysis identified alpha fetoprotein and albumin as its potential targets. CONCLUSION: These findings suggest the potential of miRNA-4525 in serum EVs as a novel biomarker for advanced RCC.

Simultaneous pembrolizumab-induced myasthenia gravis and myocarditis in a patient with metastatic bladder cancer: A case report.

We report a fatal case of pembrolizumab-induced myasthenia gravis and myocarditis in a patient with metastatic bladder cancer. A 77-year-old man was aware of eye ptosis and diplopia after three weeks from first infusion of pembrolizumab, an anti-programmed cell death protein 1 monoclonal antibodies. He was diagnosed with myasthenia gravis, because he was positive on the edrophonium test and acetylcholine receptor antibody. As his echocardiography also revealed diffuse loss in wall motion with ejection fraction 29%, he was strongly suspected myocarditis. Although he was treated with prednisone and intravenous immunoglobulin, he was suddenly in cardiac arrest and passed away.