Cross-sectional and longitudinal analyses of urinary extracellular vesicle mRNA markers in urothelial bladder cancer patients.

We designed this multi-center prospective study with the following objectives: (1) the cross-sectional validation of extracellular vesicles (EV) mRNA markers to detect urothelial bladder cancer (UBC) before transurethral resection of bladder cancer (TURBT), and (2) the longitudinal validation of EV mRNA markers to monitor non-muscle invasive bladder cancer (NMIBC) recurrence after TURBT. EV mRNA markers evaluated in this study were KRT17, GPRC5A, and SLC2A1 in addition to two additional markers from literatures, MDK and CXCR2, and measured by quantitative RT-PCR with normalization by a reference gene (ALDOB). Diagnostic performances of EV mRNA markers were compared to conventional markers. Regarding the first objective, we confirmed that EV mRNA biomarkers in urine were higher in UBC patients, particularly those with higher stage/grade tumors, than in those without UBC (n = 278 in total) and the diagnostic performance of EV mRNA MDK and KRT17 outperformed conventional biomarkers with AUC 0.760 and 0.730, respectively. Concerning the second objective, we prospectively analyzed the time courses of EV mRNA markers while NMIBC patients (n = 189) (median follow-up 19 months). The expression of EV mRNA KRT17 was significantly high in patients with recurrence, while it gradually decreased over time in those without recurrence (p < 0.01).

Use of lacosamide for focal epilepsy in a child with kidney failure undergoing peritoneal dialysis.

BACKGROUND: Lacosamide (LCM) has become commonly used for focal onset seizures due to its high tolerability and low drug interactions. Unlike patients on hemodialysis (HD), pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis (PD) are scant. CASE REPORT: A 2-year-old girl with end-stage kidney disease undergoing PD suffered prolonged focal onset seizures. The patient had congenital anomalies of the kidney and urinary tract associated with branchio-oto-renal syndrome due to an EYA1 gene mutation. She also had neurological sequelae from post-resuscitation encephalopathy at the age of one month. Antiseizure medication with few drug interactions, less impact on the neurodevelopmental state and possibility of intravenous administration was preferred. LCM met those criteria and was carefully administered. Although the patient had recurrent prolonged seizures during the titration periods, LCM could be continued without any apparent side effects. The blood levels of LCM increased linearly to the optimal level. We confirmed excretion of LCM in the PD fluid. Kidney transplantation was done three months after and her seizures were well controlled. CONCLUSIONS: LCM might be a promising option for patients undergoing PD. Due to the lower removal efficacy in PD compared with in HD, close attention should be paid to possible drug excess.

Changes in bone turnover markers after discontinuing long-term glucocorticoid administration in children with idiopathic nephrotic syndrome: a multicenter retrospective observational study.

BACKGROUND: Glucocorticoids affect bone turnover. Little is known about how bone turnover changes when glucocorticoids are discontinued following long-term administration. METHODS: This retrospective observational study was conducted on the relationship between discontinuation of long-term administration of glucocorticoid and bone turnover markers (BTMs) in patients with childhood-onset idiopathic nephrotic syndrome. Serum bone alkaline phosphatase (BAP), intact procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase-5b (TRACP-5b) were evaluated as BTMs. RESULTS: Thirty-eight pairs of BTMs at glucocorticoid administration and after discontinuation were analyzed in 29 patients. The median age at baseline was 12.4 (interquartile range, 9.0-14.5) years, and the median time from the onset of nephrotic syndrome was 5.9 (3.3-9.7) years. The mean period from prednisolone discontinuation to the measurement of BTMs after glucocorticoid discontinuation was 3.5 ± 1.0 months. Changes in BTMs after glucocorticoid discontinuation were modest when the daily prednisolone dose was < 0.25 mg/kg/day (ln BAP standard deviation [SD] score, p = 0.19; log intact P1NP SD score, p = 0.70; TRACP-5b, p = 0.95). When the daily prednisolone dose was ≥ 0.25 mg/kg/day, all BTMs increased significantly after glucocorticoid discontinuation (ln BAP SD score, p < 0.01; log intact P1NP SD score, p < 0.01; TRACP-5b, p < 0.01). CONCLUSIONS: Decreased BTMs can rise within a few months of discontinuing long-term glucocorticoid administration. When the administered glucocorticoid dose is low, changes in BTMs may be small. A higher resolution version of the Graphical abstract is available as Supplementary information.

Postoperative Adjuvant Anastrozole for 10 or 5 Years in Patients With Hormone Receptor-Positive Breast Cancer: AERAS, a Randomized Multicenter Open-Label Phase III Trial.

PURPOSE: Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on disease-free survival (DFS). PATIENTS AND METHODS: This prospective, randomized, multicenter open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients who were disease-free after treatment with either 5 years of anastrozole alone or 2-3 years of tamoxifen followed by 2-3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole for an additional 5 years or stop anastrozole. The primary end point was DFS, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with University Hospital Medical Information Network, Japan (UMIN) clinical trials registry (UMIN000000818). RESULTS: We enrolled 1,697 patients from 117 facilities between November 2007 and November 2012. Follow-up information was available for 1,593 patients (n = 787 in the continue group, n = 806 in the stop group), who were defined as the full analysis set, including 144 patients previously treated with tamoxifen and 259 patients who underwent breast-conserving surgery without irradiation. The 5-year DFS rates were 91% (95% CI, 89 to 93) in the continue group and 86% (95% CI, 83 to 88) in the stop group (hazard ratio, 0.61; 95% CI, 0.46 to 0.82; P < .0010). Notably, extended anastrozole treatment reduced the incidence of local recurrence (continue group, n = 10; stop group, n = 27) and second primary cancers (continue group, n = 27; stop group, n = 52). There was no significant difference in overall or distant DFS. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than those in the stop group, but the incidence of grade ≥3 adverse events was <1% in both groups. CONCLUSION: Continuing adjuvant anastrozole for an additional 5 years after 5 years of initial treatment with anastrozole or tamoxifen followed by anastrozole was well tolerated and improved DFS. Although no difference in overall survival was observed as in other trials, extended anastrozole therapy could be one treatment choice in postmenopausal patients with hormone receptor-positive breast cancer.

Validity of computed mean compressed fibroglandular tissue thickness and breast composition for stratification of masking risk in Japanese women.

BACKGROUND: The volumetric measurement system for mammographic breast density is a high-precision objective method for evaluating the percentage of fibroglandular tissue volume (FG%). Nonetheless, FG% does not precisely correlate with subjective visual estimation (SVE) and shows poor evaluation performance regarding masking risk in patients with comparatively thin compressed breast thickness (CBT), commonly found in Japanese women. We considered that the mean compressed fibroglandular tissue thickness (mCGT), which incorporates the CBT element into the evaluation of breast density, may better predict masking risk. METHODS: Volumetric measurements and SVEs were performed on mammograms of 108 breast cancer patients from our center. mCGT was calculated as the product of CBT and FG%. SVE was classified using the Breast Imaging-Reporting and Data System classification, 5th edition. Subsequently, the performance of mCGT, SVE, and FG% in predicting masking risk was estimated using the AUC. RESULTS: The AUC values of mCGT and SVE were 0.84 (95% confidence interval, 0.71-0.92) and 0.78 (0.66-0.86), respectively (P = 0.16). The AUC of the FG% was 0.65 (0.52-0.77), which was significantly lower than that of mCGT (P < 0.001). The sensitivity and specificity of mCGT in predicting negative detection were 89% and 71%, respectively; of SVE 83% and 61% (versus 72% and 57% with FG%), suggesting that mCGT was superior to FG% in both sensitivity and specificity, and comparable with SVE. CONCLUSIONS: Objective mCGT calculated from the volumetric measurement system will highly likely be useful in evaluating breast density and supporting visual assessment for masking risk stratification.

Validation of the Japanese version of the Body Image Scale for bladder cancer patients.

The Body Image Scale (BIS) is a 10-item tool that measures the body images of cancer patients. This study aims to validate the Japanese version of the BIS for bladder cancer patients. A multicenter cross-sectional survey was used to identify the participants, which included Japanese bladder cancer patients. The percentage of missing responses, internal consistency, and known-group validity were evaluated. The correlations between the BIS and two HRQOL instruments (the Bladder Cancer Index and the SF-12) were assessed to determine convergent validity. Among 397 patients, 221 patients were treated by transurethral resection of bladder tumor (TURBT) endoscopically, 49 patients underwent cystectomy with neobladder, and 127 patients underwent cystectomy involving stoma. The percentage of missing responses in the BIS ranged from 8.1 to 15.6%. Cronbach's α coefficient was 0.924. Higher BIS scores indicate negative body image, and the median BIS score for patients with native bladders after TURBT (0.5) was significantly lower than those of the patients with neobladder (4.0) and stoma formation (7.0), which indicated the discriminatory ability of the BIS. Each domain of the Bladder Cancer Index and the role summary score of the SF-12 correlated to the BIS scores, which confirmed the convergent validity. A range of BIS scores were identified among patients who reported similar physical summary scores and mental summary scores of the SF-12. This study confirmed the reliability and validity of the Japanese version of the BIS for bladder cancer patients.

Cooccurrence of Alport syndrome and poststreptococcal acute glomerulonephritis with improvement after steroid administration.

It is clinically possible for patients with Alport syndrome (AS) to suffer from poststreptococcal acute glomerulonephritis (PSAGN). However, there is only one report of such a patient, and he had end-stage kidney disease. Here, we describe an 8-year-old male with X-linked AS and chronic kidney disease (CKD) stage G2. He presented with diffuse edema, gross hematuria, proteinuria, and body weight gain after streptococcal pharyngitis. Blood examination showed kidney dysfunction, hypocomplementemia, and increased anti-streptolysin-O levels. His kidney function did not improve with symptomatic treatment. Therefore, we started steroid administration on the 12th day of hospitalization. Then, his kidney function improved before he was discharged. We confirmed that his complement function had recovered at a later date. Pathological evaluation showed findings of AS and PSAGN, including cellular crescents in 3/30 glomeruli on light microscopy. In addition, electron dense deposits (EDDs) were seen in not only the visceral subepithelium but also the glomerular basement intramembrane and subendothelium, some of which were hump-like. Although AS and CKD are indicated to have a poor prognosis in PSAGN, our patient recovered after administration of steroids. Our case suggests that we can consider the administration of steroids, including pulse therapy for PSAGN, when patients have, for example, crescents on pathology, severe renal dysfunction, nephrotic proteinuria, or AS with CKD, as in our case. Kidney pathology suggested that a typical hump is not seen in patients with cooccurring AS and PSAGN. After the patient's kidney function recovered, we continued to follow him.

The effect of rituximab on the quality of life of children with refractory nephrotic syndrome.

BACKGROUND: Rituximab (RTX) is an effective treatment for maintaining remission in patients with nephrotic syndrome (NS), but there are few reports on the effect of RTX treatment on quality of life (QOL). The purpose of this study was to examine the effect of periodically repeated RTX treatment from the perspective of QOL. METHODS: We systematically assessed the QOL of pediatric patients with refractory NS and parents' perceptions of their children's QOL through a 2 year RTX treatment protocol. Pediatric patients from Hokkaido University Hospital with refractory NS who met our specific criteria were enrolled between January 2015 and December 2015. The RTX infusion was performed 4 times at 6-month intervals, followed by mizoribine administration with early discontinuation of calcineurin inhibitors. Quality of life scores were measured by the Pediatric Quality of Life Inventory version 4.0 (PedsQL) at each RTX administration and evaluated 2 years later. RESULTS: Twenty-two patients were analyzed. The patients' QOL and their parents' perceptions of their QOL improved over our 2 year treatment protocol. Nevertheless, the parents' scores were lower than the patients' scores on all scales, with slower improvement. CONCLUSIONS: Our treatment protocol showed a significant improvement of QOL in patients with refractory NS. Although the risk of the RTX treatment should be considered, the treatment is useful for patients with refractory NS.

Long-term clinical characteristics and renal prognosis of children with tubulointerstitial nephritis and uveitis syndrome.

BACKGROUND: Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease, especially in children. Owing to the short-term observational period and the small number of patients analyzed in previous reports, the long-term clinical and laboratory characteristics and renal prognosis of children with TINU syndrome remain unclear. METHODS: In this retrospective observational study, we enrolled 29 children with TINU syndrome from February 1990 to February 2019. RESULTS: During the median follow-up duration of 38 months, the kidney function, urinary ß2 microglobulin-creatinine ratio (U-ß2MG/Cr), and uveitis in the patients had significantly improved at 24, 6, and 36 months after diagnosis. Higher U-ß2MG/Cr was associated with longer duration of kidney function normalization. Half of the patients required uveitis treatment for 5 years after the diagnosis. CONCLUSIONS: Patients with severe low-molecular weight proteinuria at diagnosis needed a longer duration to achieve improvements in kidney function. Uveitis has a much longer treatment period than tubulointerstitial nephritis. This study demonstrates the good prognosis of children with TINU syndrome in terms of their long-term clinical and laboratory characteristics.

Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer. METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969. FINDINGS: Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis. INTERPRETATION: These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer. FUNDING: Public Health Research Foundation (Japan), Taiho Pharmaceutical.

Coexistence of acute poststreptococcal glomerulonephritis and acute rheumatic fever in a Japanese girl with primary Sjögren's syndrome.

Although acute poststreptococcal glomerulonephritis (APSGN) and acute rheumatic fever (ARF) are well-known complications of group A streptococcus infection, concomitant occurrence of both diseases is rare. We report an 11-year-old Japanese girl with primary Sjögren's syndrome complicated by acute renal failure about 2 weeks after the onset of pharyngitis. Although histopathological findings of the kidney were not confirmative, APSGN was suggested by the spontaneous recovery of her renal function, typical latent period with high levels of antistreptolysin O and low serum levels of C3 but not of C4. In addition, cardiac hypomotility and regurgitation of the 4 valves progressed in the convalescent phase of APSGN, which was accompanied by elevation of serum C-reactive protein and plasma brain natriuretic peptide (BNP) levels. Myocarditis was suggested by delayed gadolinium-enhancement of cardiac walls on cardiac magnetic resonance imaging. She was diagnosed with APSGN and ARF and was treated with a combination of short course prednisolone and prophylactic penicillin G. There is no relapse of renal or cardiac symptoms during 6 years follow-up. Unexpected elevation of plasma BNP in a convalescent stage of APSGN suggests the development of ARF. Underlying Sjögren's syndrome (SS) may modify the histopathological findings and make it difficult to differentiate APSGN from CTD-associated nephritis such as lupus nephritis (LN) even by renal biopsy.

Health-related quality of life in Japanese patients with bladder cancer measured by a newly developed Japanese version of the Bladder Cancer Index.

INTRODUCTION: We validated a Japanese version of the Bladder Cancer Index (BCI) as a tool for measuring health-related quality of life (HRQOL) in bladder cancer patients treated with various surgical procedures. METHODS: The reliability and validity of the Japanese BCI were examined in 397 Japanese patients with bladder cancer via cross-sectional analysis. The patients simultaneously completed the Short Form (SF)-12, EQ-5D, and the Functional Assessment of Cancer Therapy-General and Bladder (FACT-G and FACT-BL). The differences in BCI subscales among various treatment groups were analyzed. RESULTS: This study involved 397 patients (301 males and 96 females), with a mean age of 70 years and a median disease duration of 29 months (IQR: 12-66 months). Of these patients, 221 underwent transurethral resection of a bladder tumor, and 176 patients underwent radical cystectomy (ileal conduit: 101 patients, ileal neobladder: 49, and ureterostomy: 26). Cronbach's alpha coefficient was ≥ 0.78 for all subscales, except the bowel bother subscale. Despite moderate correlations being detected between the function and bother score in urinary and bowel domains, the sexual function score was inversely correlated with the sexual bother score (r = - 0.19). A missing value percentage of > 15% was associated with old age (p < 0.05). The mean domain scores differed significantly among distinct clinically relevant treatment groups. CONCLUSIONS: Although revisions are needed to make it easier for elderly patients to comprehend, we confirmed the reliability and validity of the Japanese BCI. The Japanese BCI could be used for cross-cultural assessments of HRQOL in bladder cancer patients.

Onset mechanism of a female patient with Dent disease 2.

BACKGROUND: Approximately 15% of patients with Dent disease have pathogenic variants in the OCRL gene on Xq25-26, a condition that is referred to as Dent disease 2 (Dent-2). Dent-2 patients sometimes show mild extrarenal features of Lowe syndrome, such as mild mental retardation, suggesting that Dent-2 represents a mild form of Lowe syndrome. To date, eight female patients with Lowe syndrome have been reported, but no female Dent-2 patients have been reported. METHODS: In this study, we performed genetic testing of the first female Dent-2 patient to detect the presence of an OCRL variant. Aberrant splicing was demonstrated by in vivo, in vitro, and in silico assays, and skewed X-chromosome inactivation (XCI) in our patient and asymptomatic mothers of three Lowe patients with the heterozygous OCRL variant was evaluated by HUMARA assays using genomic DNA and RNA expression analysis. RESULTS: Our patient had an OCRL heterozygous intronic variant of c.1603-3G > C in intron 15 that led to a 169-bp insertion in exon 16, yielding the truncating mutation r.1602_1603ins (169) (p.Val535Glyfs*6) in exon 16. HUMARA assays of leukocytes obtained from this patient demonstrated incompletely skewed XCI (not extremely skewed). On the other hand, the asymptomatic mothers of 3 Lowe patients demonstrated random XCI. These results may lead to our patient's Dent-2 phenotype. CONCLUSIONS: This is the first report of a female patient clinically and genetically diagnosed with Dent-2 caused by an OCRL heterozygous splicing site variant and skewed XCI. Skewed XCI may be one of the factors associated with phenotypic diversity in female patients with Lowe syndrome and Dent-2.

Individualized concept for the treatment of autosomal recessive polycystic kidney disease with end-stage renal disease.

Management of children with autosomal recessive polycystic kidney disease (ARPKD) who develop end-stage renal disease (ESRD) remains challenging because of concomitant liver disease. Patients with recurrent cholangitis are candidates for liver-kidney transplantation, while the treatment for patients with splenomegaly and pancytopenia due to portal hypertension is controversial. Herein, we report 7 children who were treated using an individualized treatment strategy stratified by liver disease. Two patients with recurrent cholangitis underwent sequential liver-kidney transplantation, while 4 patients with splenomegaly and pancytopenia but without recurrent cholangitis underwent splenectomy followed by isolated kidney transplantation. The remaining patient, who did not have cholangitis and pancytopenia, underwent isolated kidney transplantation. Blood cell counts were normalized after splenectomy was performed at the median age of 8.7 (range, 7.4-11.7) years. Kidney transplantation was performed at the median age of 8.8 (range, 1.9-14.7) years in all patients. Overwhelming post-splenectomy infections and cholangitis did not occur during the median follow-up period of 6.3 (range, 1.0-13.2) years. The estimated glomerular filtration rate at the last follow-up was 53 (range, 35-107) mL/min/1.73 m2 . No graft loss occurred. Our individualized treatment strategy stratified by recurrent cholangitis and pancytopenia can be a feasible strategy for children with ARPKD who develop ESRD and warrants further evaluation.

Glucose metabolism disorders in children with refractory nephrotic syndrome.

BACKGROUND: Patients with refractory nephrotic syndrome (NS) are at high risk of medication-induced glucose metabolism disorders, because of their long-term use of diabetogenic medications, particularly glucocorticoids and calcineurin inhibitors (CNIs). However, there have been no comprehensive evaluations of glucose metabolism disorders in pediatric patients with refractory NS. Moreover, glucocorticoids and CNIs could not be discontinued in these patients until the effectiveness of rituximab on refractory NS was shown, and therefore, there has been limited opportunity to evaluate glucose metabolism disorders after discontinuation of these medications. METHODS: Consecutive pediatric patients who started rituximab treatment for refractory NS were enrolled. Their glucose metabolism conditions were evaluated using the oral glucose tolerance tests (OGTT) and HbA1c levels at the initiation of rituximab treatment. Patients with glucose metabolism disorders at the first evaluation were reevaluated after approximately 2 years. RESULTS: Overall, 57% (20/35) of study patients had glucose metabolism disorders, and 40% (8/20) of these patients were detected only by their 2-h OGTT blood glucose levels and not by their fasting blood glucose or HbA1c levels. Non-obese/non-overweight patients had significantly more glucose metabolism disorders than obese/overweight patients (p = 0.019). In addition, glucose metabolism disorders in 71% (10/14) of patients persisted after the discontinuation of glucocorticoids and CNIs. CONCLUSIONS: Whether the patient is obese/overweight or not, patients with refractory NS are at high risk of developing glucose metabolism disorders, even in childhood. Non-obese/non-overweight patients who are at high risk of diabetes need extra vigilance.

Mesangial C4d deposition at diagnosis in childhood immunoglobulin A nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is a major cause of end-stage renal disease. Complement activation via the lectin pathway influences outcomes in IgAN. We examined the association of glomerular C4d deposition with clinicopathological severity at diagnosis and the disappearance of proteinuria in Japanese pediatric IgAN patients. METHODS: We retrospectively analyzed 25 children newly diagnosed with IgAN at Hokkaido University Hospital. We evaluated glomerular C4d immunofluorescent staining at diagnosis. We compared clinical findings, pathological findings (based on Oxford classification), and the disappearance of proteinuria within 24 months after renal biopsy between C4d-positive and C4d-negative patients. RESULTS: Glomerular C4d staining was observed in 14 patients (56.0%). C4d-positive patients had significantly higher proteinuria at diagnosis than C4d-negative patients (2.03 g/gCr vs 0.78 g/gCr; P = 0.005). The number of glomeruli with segmental glomerulosclerosis or adhesion (8.0% vs 0.0%; P = 0.046) and the extent of tubular atrophy/interstitial fibrosis (9.46% vs 2.86%; P = 0.031) were significantly increased in C4d-positive patients compared with C4d-negative patients. Further, the proportion of patients with modified T1 (>10%) was significantly higher in the C4d-positive group than the C4d-negative group. There was no significant difference, however, in the disappearance rate of proteinuria at 24 months after renal biopsy between groups (64% vs 82%; P = 0.149). CONCLUSIONS: Glomerular C4d deposition was associated with clinicopathological severity at diagnosis in Japanese pediatric patients with IgAN. Glomerular C4d deposition, however, was not a predictor of the disappearance of proteinuria within 24 months after diagnosis in Japanese pediatric patients with IgAN.

Polygon method: A systematic margin assessment for breast conservation.

BACKGROUND: Radiation therapy (RT) for women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery (BCS) may be overtreatment for some, especially for those in which DCIS is eradicated, and ipsilateral breast tumor recurrence (IBTR) risk approaches the contralateral breast cancer (CBC) level. The aim of this study was to clarify whether the polygon method, a new systematic method of en face (tangential, shaved) margin assessment, can identify a subset of DCIS that can be safely treated by BCS alone. METHODS: A key tool of the polygon method is an adjustable mold that prevents the "pancake phenomenon" (flattening) of breast tissue after surgical removal so that the specimen is fixed in the shape of a polygonal prism. This preanalytical procedure enables us to command a panoramic view of entire en face margins 3-5-mm deep from the real peripheral cut surfaces. Competing risk analysis was used to quantify rates of IBTR and CBC and to evaluate risk factors. RESULTS: From 2000 to 2013, we identified 146 DCIS patients undergoing BCS with a contralateral breast at risk. In 100 DCIS patients whose margin was negative by the polygon method, 5 IBTR (3 DCIS and 2 invasive ductal carcinoma [IDC]) and 10 CBC (6 DCIS and 4 IDC) cases were identified during a median follow-up of 7.6 years (range, 0.9-17.4). Five- and 10-year cumulative incidence rates were 3.0% and 5.3% for IBTR, and 7.1% and 13.3% for CBC, respectively. Thus, patients with a negative margin consistently showed at least twofold lower IBTR than CBC despite omission of RT. CONCLUSIONS: Japanese women classified with a negative margin by the polygon method show a very low risk of IBTR and account for approximately half of CBC cases. In this subset of DCIS patients, additional RT is not beneficial.