Learning more from the inter-rater reliability of interstitial fibrosis assessment beyond just a statistic.

Interstitial fibrosis assessment by renal pathologists lacks good agreement, and we aimed to investigate its hidden properties and infer possible clinical impact. Fifty kidney biopsies were assessed by 9 renal pathologists and evaluated by intraclass correlation coefficients (ICCs) and kappa statistics. Probabilities of pathologists' assessments that would deviate far from true values were derived from quadratic regression and multilayer perceptron nonlinear regression. Likely causes of variation in interstitial fibrosis assessment were investigated. Possible misclassification rates were inferred on reported large cohorts. We found inter-rater reliabilities ranged from poor to good (ICCs 0.48 to 0.90), and pathologists' assessments had the worst agreements when the extent of interstitial fibrosis was moderate. 33.5% of pathologists' assessments were expected to deviate far from the true values. Variation in interstitial fibrosis assessment was found to be correlated with variation in interstitial inflammation assessment (r2 = 32.1%). Taking IgA nephropathy as an example, the Oxford T scores for interstitial fibrosis were expected to be misclassified in 21.9% of patients. This study demonstrated the complexity of the inter-rater reliability of interstitial fibrosis assessment, and our proposed approaches discovered previously unknown properties in pathologists' practice and inferred a possible clinical impact on patients.

Unsatisfactory reproducibility of interstitial inflammation scoring in allograft kidney biopsy.

Interstitial inflammation scoring is incorporated into the Banff Classification of Renal Allograft Pathology and is essential for the diagnosis of T-cell mediated rejection. However, its reproducibility, including inter-rater and intra-rater reliabilities, has not been carefully investigated. In this study, eight renal pathologists from different hospitals independently scored 45 kidney allograft biopsies with varying extents of interstitial inflammation. Inter-rater reliabilities and intra-rater reliabilities were investigated by kappa statistics and conditional agreement probabilities. Individual pathologists' scoring patterns were examined by chi-squared tests and proportions tests. The mean pairwise kappa values for inter-rater reliability were 0.27, 0.30, and 0.26 for the Banff i score, ti score, and i-IFTA, respectively. No rater pair performed consistently better or worse than others on all three scorings. After dichotomizing the scores into two groups (none/mild and moderate/severe inflammation), the averaged conditional agreements ranged from 47.1% to 50.0%. The distributions of the scores differed, but some pathologists persistently scored higher or lower than others. Given the important role of interstitial inflammation scoring in the diagnosis of T-cell mediated rejection, transplant practitioners should be aware of the possible clinical implications of the far-from-optimal reproducibility.

Outcome of Brain Lymphoma in a High Epstein-Barr Virus-Prevalence Country After Kidney Transplantation.

BACKGROUND: The incidence of post-transplant lymphoproliferative disorder (PTLD) in adult kidney transplant (KTx) recipients is less common in Taiwan. In our institute, we observed that brain lymphoma was the most notorious type. METHODS: The study describes the clinical, histologic, and radiological features of primary central nervous lymphoma (PCNSL) and the outcomes and associations with Epstein-Barr virus (EBV) infection in our center. RESULTS: Among 1470 KTx recipients, 5 patients had tissue-proven brain lymphoma (0.34%). The brain pathology disclosed diffuse large B-cell lymphoma in all patients. EBV was detected through in situ hybridization for Epstein-Barr encoding region (EBER) to disclose the EBV inclusion in the nuclei of lymphoma cells. The first treatment step was the reduction of immunosuppressants; 4 patients received whole-brain radiotherapy after complete resection of PCNSL, and 1 received concurrent chemoradiotherapy. Only one patient had poor performance status at the time of diagnosis and had a poor response to treatment with steroids. Four patients survived (mean 36.5 months, range 8.6 to 57.6 months), but one died after rapid neurologic deterioration. CONCLUSION: Epstein-Barr virus inclusion was found in PCNSL in our patients; however, the role of EBV in PCNSL remains to be clarified. Post-transplant lymphoproliferative disorder is a rare malignancy after KTx with a predilection of brain involvement in Taiwan. We report a successful care experience in a patient with primary CNS lymphoma with better survival.

Renal Histopathology Associated With Kidney Failure and Mortality in Patients With Lupus Nephritis: A Long-Term Real-World Data Study.

OBJECTIVE: Lupus nephritis (LN), a common manifestation of systemic lupus erythematosus, is associated with a higher risk of kidney failure and death. The renal pathology of LN helps elucidate the severity of inflammation and the extent of irreversible damage. We aimed to identify histologic variables that correlate with risks of kidney failure and mortality. METHODS: Between 2006 and 2019, a total of 526 patients with LN were enrolled. Renal pathology was classified according to the International Society of Nephrology/Renal Pathology Society classification. Components of activity and chronicity indices were analyzed to determine which variables correlated with an increased risk of kidney failure and death, with the adjustment of potential confounders. RESULTS: During the follow-up period (median 7.5, IQR 3.5-10.7 years), 58 patients progressed to kidney failure and 64 died. In the multivariate Cox regression analysis, tubular atrophy (hazard ratio [HR] 2.28, 95% CI 1.66-3.14) and tubulointerstitial inflammation (HR 3.13, 95% CI 1.34-7.33) predicted kidney failure. The renal outcome was even worse if tubular atrophy and tubulointerstitial inflammation coexisted (10-year kidney survival rate: 63.22%). The presence of cellular crescents was associated with an increased risk of death in male patients with LN (HR 1.91, 95% CI 1.02-3.57), whereas the presence of fibrous crescents predicted death in female patients with LN (HR 5.70, 95% CI 1.61-20.25). CONCLUSION: Histologic variables of renal biopsy in LN could be regarded as prognostic indicators for kidney failure and mortality.

Extraskeletal Myxoid Chondrosarcomas: The Uncommon Clinicopathologic Manifestations and Significance of TAF15::NR4A3 Fusion.

Extraskeletal myxoid chondrosarcoma (EMC) is an ultrarare sarcoma typically exhibiting myxoid/reticular histology and NR4A3 translocation. However, morphologic variants and the relevance of non-EWSR1::NR4A3 fusions remain underexplored. Three challenging pan-Trk-expressing cases, featuring cellular to solid histology, were subjected to RNA exome sequencing (RES), unveiling different NR4A3-associated fusions. Alongside RES-analyzed cases, fluorescence in situ hybridization was performed to confirm 58 EMCs, with 48 available for pan-Trk immunostaining and KIT sequencing. Except for 1 (2%) NR4A3-rearranged EMC without identifiable partners, 46 (79%), 9 (16%), and 2 (3%) cases harbored EWSR1::NR4A3, TAF15::NR4A3, and TCF12::NR4A3 fusions, respectively. Five EWSR1::NR4A3-positive EMCs occurred in the subcutis (3) and bone (2). Besides 43 classical cases, there were 8 cellular, 4 rhabdoid/anaplastic, 2 solid, and 1 mixed tumor-like variants. Tumor cells were oval/spindle to pleomorphic and formed loose myxoid/reticular to compact sheet-like or fascicular patterns, imparting broad diagnostic considerations. RES showed upregulation of NTRK2/3, KIT, and INSM1. Moderate-to-strong immunoreactivities of pan-Trk, CD117, and INSM1 were present in 35.4%, 52.6%, and 54.6% of EMCs, respectively. KIT p. E554K mutation was detected in 2/48 cases. TAF15::NR4A3 was significantly associated with size >10 cm (78%, P = .025). Size >10 cm, moderate-to-severe nuclear pleomorphism, metastasis at presentation, TAF15::NR4A3 fusion, and the administration of chemotherapy portended shorter univariate disease-specific survival, whereas only size >10 cm (P = .004) and metastasis at presentation (P = .032) remained prognostically independent. Conclusively, EMC may manifest superficial or osseous lesions harboring EWSR1::NR4A3, underrecognized solid or anaplastic histology, and pan-Trk expression, posing tremendous challenges. Most TAF15::NR4A3-positive cases were >10 cm in size, ie, a crucial independent prognosticator, whereas pathogenic KIT mutation rarely occurred.

Improved Progression-Free Survival Associated with Tumor-Infiltrating Lymphocytes in High-Grade Endometrial Cancer.

Tumor-infiltrating lymphocytes (TILs) have emerged as a prognostic marker in endometrial cancer (EC). However, the role of TILs in EC with distinct histology grades and molecular types (such as mismatch repair [MMR] deficiency) has not yet been made clear. We retrospectively included 237 patients with primary EC who underwent a standard staging operation of laparoscopic or laparotomy total hysterectomy and bilateral salpingo-oophorectomy for analyses. An independent pathologist who was blind to the study patients' information reviewed the pathologic slides to assess TILs according to the method introduced by the International Immuno-Oncology Biomarkers Working Group in 2017. The outcomes of interest included both progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method was used to determine the curves of PFS and OS according to TILs, and also in the relevant subgroups (low-grade vs. high-grade, MMR-proficient vs. MMR-deficient). After a median follow-up duration of 1.82 years, 18 patients had experienced either disease progression or death. Overall, TILs (+) were not associated with PFS or OS. We did observe, however, that TILs (+) were associated with a better PFS (p = 0.045) in patients with high-grade EC, but not in those with low-grade tumors (p = 0.733). The effect of TILs on PFS was not observed in patients with MMR-proficient (p = 0.347) or MMR-deficient (p = 0.168) EC. TILs were associated with a better PFS in patients with high-grade EC. Our results suggest that TILs may be a potential prognostic marker in these patients.

Patterns of biopsy-proven renal diseases in geriatric patients: A single medical center experience.

The elderly population is expanding rapidly, and that has become a major healthcare burden in terms of chronic kidney disease. The distribution patterns of kidney diseases in these elderly patients remain largely unclear. Here, we compared biopsy-based renal disease patterns between elderly and nonelderly patients. We performed a single-center, retrospective study (1992-2008) on biopsy-proven renal diseases to compare results between geriatric patients (age ≥ 65 years; n = 254) and nongeriatric patients (18 ≤ age < 65 years; n = 2592). Renal pathology was interpreted by pathologists based on light microscopy, immunofluorescence, and electron microscopy. The ages of the geriatric and nongeriatric groups were 71.8 ±â€…4.5 (65.1-87.3) and 39.7 ±â€…17.6 (18-64.9) years, respectively, and 74% and 41% of them, respectively, were men. In the geriatric group, the most frequent diagnosis was membranous nephropathy (46.1%), followed by minimal change disease/focal segmental glomerulosclerosis (16.9%), diabetic nephropathy (8.3%), hypertensive nephrosclerosis (7.5%), and IgA nephropathy (5.9%). The geriatric group had more membranous nephropathy and less lupus nephritis and IgA nephropathy than the nongeriatric group. Furthermore, the 5-year survival rate of the geriatric group was significantly low. Our results demonstrated the different distributions of renal biopsy patterns in geriatric patients diagnosed with acute or chronic progressive kidney injury and proteinuria through renal biopsy.

Decoy Receptor 3 Suppresses T-Cell Priming and Promotes Apoptosis of Effector T-Cells in Acute Cell-Mediated Rejection: The Role of Reverse Signaling.

Background: Decoy receptor 3 (DcR3) belongs to the tumor necrosis factor (TNF) receptor superfamily and neutralizes TNF ligands, including FasL and TRAIL, to prevent T activation during T-cell priming. However, the cellular mechanisms underlying acute cell-mediated rejection (ACMR) remain unknown. Methods: We generated DcR3 transgenic (Tg) mice and mice with high DcR3 expression (HDE) to study both in vivo and in vitro. FasR RNA knockdown in immortalized CD4+CD8+ T-cells was used to survey the role of DcR3 on FasR/Fas-associated protein with death domain (FADD)/caspase 8 pathway and its cross-link to TNF receptor-associated factor 1 (TNFR1)-associated death domain protein (TRADD) in suppressing TNFR1. TNF/TRADD knockout mice were used to show the importance of TNF adaptor protein. Results: DcR3.Fc suppressed C57BL/6 female T-cell activation and transformation into CD4+CD69+, CD4+CD44+, and CD4+CD25+Foxp3+ when compared with isotype IgG1 and its co-treatment with FasL/TRAIL after exposing to bone marrow-derived dendritic cells (BMDCs) that carried alloantigen with male H-Y and minor antigenic determinant. Interleukin-17 and interferon-γ productions by BMDC-activated T-cells were lowered after co-treating with DcR3.Fc. DcR3.Fc induced effector T-cells (Teffs) and was susceptible to FasR-mediated apoptosis through the FADD/TRADD/caspase 8 pathway. After exposing to DcR3.Fc, TRADD was silenced, likely turning down the inflammatory response. The systemic effects of DcR3 Tg mice and HDE phenotype induced by the promoter of cytomegalovirus not only attenuated ACMR severity but also ameliorated the high serum creatinine and blood urea nitrogen levels even with high T-cell exposure frequencies. Besides this, DcR3 has minor biological effects on both MHC-matched and MHC-mismatched models. Conclusions: High DcR3 doses protect renal tubular epithelial cells from acute T-cell attack during the T-cell priming stage via interfering with TNF ligand-mediated reverse signaling and possibly promoting Teff apoptosis through FasR upregulation. Our findings supported that the decoy receptor is involved in T-cell modulation in kidney transplant rejection.

End-to-end interstitial fibrosis assessment of kidney biopsies with a machine learning-based model.

BACKGROUND: The extent of interstitial fibrosis in the kidney not only correlates with renal function at the time of biopsy but also predicts future renal outcome. However, its assessment by pathologists lacks good agreement. The aim of this study is to construct a machine learning-based model that enables automatic and reliable assessment of interstitial fibrosis in human kidney biopsies. METHODS: Validated cortex, glomerulus and tubule segmentation algorithms were incorporated into a single model to assess the extent of interstitial fibrosis. The model performances were compared with expert renal pathologists and correlated with patients' renal functional data. RESULTS: Compared with human raters, the model had the best agreement [intraclass correlation coefficient (ICC) 0.90] to the reference in 50 test cases. The model also had a low mean bias and the narrowest 95% limits of agreement. The model was robust against colour variation on images obtained at different times, through different scanners, or from outside institutions with excellent ICCs of 0.92-0.97. The model showed significantly better test-retest reliability (ICC 0.98) than humans (ICC 0.76-0.94) and the amount of interstitial fibrosis inferred by the model strongly correlated with 405 patients' serum creatinine (r = 0.65-0.67) and estimated glomerular filtration rate (r = -0.74 to -0.76). CONCLUSIONS: This study demonstrated that a trained machine learning-based model can faithfully simulate the whole process of interstitial fibrosis assessment, which traditionally can only be carried out by renal pathologists. Our data suggested that such a model may provide more reliable results, thus enabling precision medicine.

Change of Renal Gallium Uptake Correlated with Change of Inflammation Activity in Renal Pathology in Lupus Nephritis Patients.

BACKGROUND: Lupus nephritis (LN) often lead to end-stage renal disease in systemic lupus erythematosus patients. This study aimed to investigate the clinical application of renal gallium-67 scans for determining renal histological parameters in LN patients. METHODS: Between 2006 and 2018, 237 biopsy-proven and 35 repeat biopsies LN patients who underwent renal gallium scans before or after biopsy were included for analysis. The classification and scoring of LN were assessed according to the International Society of Nephrology/Renal Pathology Society. A delayed 48-h gallium scan was performed and interpreted by semiquantitative methods using left kidney/spine (K/S) ratio. The renal histological results were compared with gallium uptake. RESULTS: Out of 237 participants, 180 (76%) had proliferative LN. Baseline gallium left K/S ratio was significantly higher in class IV LN as compared to class III (median (interquartile range, IQR): 1.16 (1.0-1.3), 0.95 (0.9-1.1), respectively, p < 0.001). Furthermore, changes in gallium uptake between two biopsies were positively correlated with changes activity index (r = 0.357, p = 0.035), endocapillary hypercellularity (r = 0.385, p = 0.032), and neutrophils infiltration (r = 0.390, p = 0.030) in renal pathology. CONCLUSIONS: Renal gallium uptake is associated with active inflammation in LN. Changes in renal gallium uptake positively correlated with changes in activity index in renal pathology.

Clinical manifestation of multiple wasp stings with details of whole transcriptome analysis: Two case reports.

INTRODUCTION: Multiple wasp stings is an emergency result from systemic reactions to the toxin with a wide range of manifestations, and we presented 2 patients with distinct clinical and transcriptomic findings. PATIENT CONCERNS: Two patients without systemic disease presented with nearly 90 painful papules after attacked by a swarm of wasps (Vespa basalis). DIAGNOSIS: Patient 1 was a 44-year-old healthy male whose clinical manifestations mainly comprised hemolysis, hepatic injury, rhabdomyolysis, and acute kidney injury. Patient 2 was a 49-year-old healthy female who presented with severe acute respiratory distress syndrome (ARDS) in addition to certain clinical manifestations that were also found in patient 1. We used ribo- nucleic acid sequencing (RNA-Seq) to characterize the inflammatory responses of 2 patients with distinct clinical manifestations after multiple wasp stings. INTERVENTIONS: Both 2 patients received 5 sessions of plasmapheresis, and patient-1 further received mechanical ventilation for 8 days as well as 8 sessions of hemodialysis until day 17. OUTCOMES: Both patients recovered uneventfully after the aforementioned management. We used RNA-Seq to demonstrate a largely regulated neutrophil-predominated immune response in patient 1. In patient 2, we found a profound neutrophilc response on week 1 and a robust neutrophilic as well as pro-inflammatory responses on week 2. Furthermore, we found increased expression of signals that were associated with renal system process on week 2. CONCLUSION: In conclusion, we report 2 patients who manifested with shared and distinct presentations after an attack by the same swarm of wasps. Both patients had hemolysis, rhabdomyolysis, hepatic injury and acute kidney injury, and 1 patient had ARDS. The whole transcriptomic analyses were consistent with the distinct clinical manifestation, and these results suggest the potential of RNA-Sequencing to disentangle complex inflammatory responses in patients with multiple wasp stings. Plasmapheresis and corticosteroid were administered to both patients and case 2 also underwent 8 sessions of hemodialysis.

Ongoing donor-transmitted diabetic kidney disease in kidney transplant recipients with fair sugar control: a single center retrospective study.

BACKGROUND: Transplantation with a diabetic donor kidney may have some benefits compared to remaining on the waitlist for selected patients. However, we found that some kidney transplant recipients have ongoing donor-transmitted diabetic kidney disease (DT-DKD) despite fair blood sugar control. This study aimed to survey the incidence and clinical pattern of DT-DKD in kidney transplant recipients. METHODS: We retrospectively reviewed the medical records of kidney transplantations in our hospital. We found 357 kidney transplantations from February 2006 to April 2018. Among these, 23 (6.4%) diabetic donor kidney transplantations were done in the study period. RESULTS: Among the 23 recipients, 6 (26.1%) displayed biopsy-proven DKD. Recipients with biopsy-proven DKD had longer dialysis vintage, higher proteinuria amount, lower last estimated glomerular filtration rate (eGFR), and a more rapid decline in the eGFR. The median fasting blood sugar level in the biopsy-proven DKD group was unexpectedly lower than the non-DKD group. Most of the pre-implantation frozen sections in biopsy-proven DKD group showed diabetic lesions worse than diabetic nephropathy (DN) class IIa. In the biopsy-proven DKD group, 5 recipients had no history of diabetes before or after transplantation. Among the 23 recipients, 5 (21.7%) were diagnosed with DT-DKD. Serial post-transplant biopsies showed the histological progression of allograft DN. CONCLUSIONS: To the best of our knowledge, this is the first study to report the phenomenon of ongoing DT-DKD in kidney transplant recipients with fair blood sugar control. The zero-time pre-transplant kidney biopsy may be an important examination before the allocation of diabetic donor kidneys. Further study is needed to elucidate the possible mechanism of ongoing DT-DKD in non-diabetic recipients with fair blood sugar control as well as the impaction of pre-implantation diabetic lesion on the graft outcome.

Crescents formations are independently associated with higher mortality in biopsy-confirmed immunoglobulin A nephropathy.

BACKGROUND AND OBJECTIVES: Immunoglobulin A Nephropathy (IgAN) is the most common type of glomerulonephritis with variable renal outcome. The association between IgAN and patient survival is limited. The effect of crescents on patient survival was never studied. MATERIALS: We conducted a retrospective cohort study between January 2003 and December 2013. All patients with the biopsy-proved IgAN was enrolled for the analysis of patient survival and renal survival. Cox regression model was used analyze the associated factors for patient survival. RESULTS: All 388 participants with IgAN were enrolled, in which 45 patients with crescents. The mean percentage of glomeruli involvement was 23±18.9%. After long-term follow-up, crescents group had both worse renal (p = 0.034) and patient survivals (p = 0.016). In univariate Cox regression model, the age (HR = 1.08, 95% CI = 1.05-1.12, p<0.001), crescents (HR = 3.93, 95% CI = 1.18-13.07, p = 0.025), serum albumin (HR = 0.023, 95%CI = 0.11-0.50, p<0.001), blood total protein (HR = 0.46, 95%CI = 0.28-0.75, p = 0.002), HDL (HR = 0.95, 95%CI = 0.91-0.99, p = 0.009), daily urine protein (HR = 1.14, 95%CI = 1.01-1.29, p = 0.038), urine PCR (HR = 1.07, 95%CI = 1.02-1.12, p = 0.003), serum IgM (HR = 0.98, 95%CI = 0.96-1.00, p = 0.036), BUN (HR = 1.02, 95%CI = 1.01-1.02, p = 0.005), and eGFR (HR = 0.097, 95%CI = 0.94-0.99, p = 0.0011) were associated with patient survival. After multivariate Cox regression analysis, age (HR = 1.08, 95%CI = 1.01-1.13, p = 0.013), crescents (HR = 5.57, 95%CI = 1.14-29.05, p = 0.034), and HDL (HR = 0.94, 95%CI = 0.90-0.99, p = 0.026) were associated with patient survival. Crescents IgAN is with the highest risk (up to 5.75 of HR) for patient mortality. CONCLUSIONS: The major strengths of the present study is that crescents IgAN had worse patient survival compared to non-crescents IgAN. Clinicians should be more careful to care patients with crescents IgAN.

Calcifying fibrous tumour: An IgG4-related disease or not?

Calcifying fibrous tumour (CFT) has some of the histopathological features, such as abundant plasma cells and stromal fibrosis, that are exhibited by IgG4-related diseases (IgG4-RD). The possible role of IgG4-positive plasma cells in calcifying fibrous tumour was investigated. The aim of this study was to determine any potential relationship between IgG4-RD and CFT. Thirteen cases with a total of 16 CFTs were reviewed. Lesion samples were immunostained with anti-IgG4 and anti-IgG antibodies. The number of IgG4-positive and IgG-positive plasma cells (IgG + PC) and their ratios were estimated. Plasma cells were found in all tumours. IgG4-positive plasma cells ranged from 0 to 71 per high-power field (HPF; mean 17.8/HPF), and IgG + PC ranged from 2 to 93/HPF (mean 42.6/HPF). The IgG4/IgG ratio ranged from 0% to 80% (mean 29%). There were seven tumours with the ratio of IgG4/IgG + PC that exceeded 40%. Various degrees of stromal fibrosis were present in eight tumours. All tumours have variable calcification. The histopathological features of CFT were found to be similar to those of IgG4-RD. Some CFT also showed a high number of IgG4-positive plasma cells, and the ratio of IgG4/IgG + PC exceeded 40%, most notably in patients with concomitant inflammatory or autoimmune disease. The long-term follow-up showed no evidence of IgG4-RD in any of these patients. Our findings suggest that while CFT overlaps morphologically with IgG4-RD, it probably should not be classified as an IgG4-RD.

Treatment of chronic active antibody-mediated rejection in renal transplant recipients - a single center retrospective study.

BACKGROUND: Chronic active antibody-mediated rejection is a major etiology of graft loss in renal transplant recipients. However, there is no consensus on the optimal treatment strategies. METHODS: Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of chronic active antibody-mediated rejection. The patients were divided into two groups according to treatment strategy: Group 1 received aggressive treatment (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy); and group 2 received supportive treatment. RESULTS: From February 2009 to December 2017, a total of 82 patients with biopsy-proven chronic antibody mediated rejection were identified. Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2 (P = 0.015 by log-rank test). Adverse event-free survival was lower in group 1, whereas patient survival was not significantly different. Proteinuria and supportive treatment were independent risk factors for graft loss in multivariate analysis. CONCLUSIONS: Aggressive treatment was associated with better graft outcome. However, higher incidence of adverse events merit personalized treatment, especially for those with higher risk of infection. Appropriate prophylactic antibiotics are recommended for patients undergoing aggressive treatment.

Serologic and Histologic Predictors of Long-Term Renal Outcome in Biopsy-Confirmed IgA Nephropathy (Haas Classification): An Observational Study.

Background and objective: The Haas classification of IgA nephropathy should be validated for Asian populations. More detailed and newer predictions regarding renal outcome of IgA nephropathy remains mandatory. Materials: We conducted a retrospective cohort study between January 2003 and December 2013. Clinical, Pathological, and laboratory data were all collected via available medical records. A Mann-Whitney U test was used for continuous variables and the Chi-square test was implemented for categorical variables. A Kaplan-Meier curve was put in place in order to determine patient survival and renal survival. The Youden index and Cox proportional hazard regression were used to investigate the possible factors for renal survival and predictive power. Results: All 272 renal biopsy-confirmed IgAN patients were enrolled for further studies. The univariate analysis showed that risk factors for poor renal outcome included stage 4-5 of Haas classification (HR = 3.67, p < 0.001), a poor baseline renal function (HR = 1.02 and p < 0.001 for higher BUN; HR = 1.14 and p < 0.001 for higher serum creatinine; HR = 0.95, p < 0.001 for higher eGFR), IgG ≤ 907 (HR = 2.29, p = 0.003), C3 ≤ 79.7 (HR = 2.76, p = 0.002), a higher C4 (HR = 1.02, p = 0.026), neutrophil-to-lymphocyte ratio > 2.75 (HR = 2.92, p < 0.001), and a platelet-to-lymphocyte ratio ≥ 16.06 (HR = 2.02, p = 0.012). A routine-checked markers, such as neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, in order to predict the renal outcome, is recommended. Conclusions: This is the first study to demonstrate that Haas classification is also useful for establishing predictive values in Asian groups. A lower serum IgG (≤907 mg/dL) and serum C3 (≤79.7 mg/dL) were both risk factors for poor renal outcome. Additionally, this is the first study to reveal that serum C4 levels, an NLR > 2.75 and a PLR > 16.06, S could suggest poor renal outcome.

Low Expression of Transforming Growth Factor ß in the Epithelium of Barrett's Esophagus.

BACKGROUND: The aim of this study was to investigate the expression of transforming growth factor ß (TGF-ß) in the different stages of Barrett's esophagus (BE). METHODS: Paired endoscopic esophageal biopsy samples were obtained from patients with BE prospectively. Subjects were classified into three groups: BE, BE with dysplasia, and adenocarcinoma (AC) arising from BE. Biopsy specimens over normal esophageal epithelium and gastric cardiac epithelium of limited cases were done. Four cell lines, HETA1 (human esophageal epithelium), CA-A and CP-C (non-dysplastic metaplasia), and OE33 (AC) were analyzed for quantitative mRNA and Western blotting of TGF-ß. RESULTS: All 30 subjects with BE were enrolled. Expression of TGF-ß mRNA in BE were significantly (P < 0.01) lower than that in the normal esophagus and cardiac epithelium. The BE tissue showed a lower positive ratio of TGF-ß immunohistochemical (IHC) stain than the cardiac epithelium. The expression of TGF-ß mRNA in the cell lines CA-A, CP-3, OE-33, was significantly (P < 0.05) lower than that in the cell line HETA-1. The Western blotting result showed lower TGF-ß protein expression of the cell lines CA-A, CP-3, and OE-33. CONCLUSIONS: The expression of TGF-ß was lower in the tissue of BE.

What does power Doppler signal indicate in rheumatoid synovitis? A point of view from synovial histopathology.

To clarify the nature of power Doppler (PD) signals in rheumatoid synovium and to establish the connection between PD signals and active inflammation using synovial histopathology. Ten adult patients (median age 57.0 years, 9 women and one man) with rheumatoid arthritis (RA) were enrolled and received ultrasound (US) examinations. US-guided synovial biopsies using core needle were performed in 7 knees, 2 wrists and one elbow. Each patient had one joint biopsied. In total, 11 synovial specimens were obtained for hematoxylin and eosin staining and histopathologic examinations. The US examinations revealed prominent synovial hypertrophy in all biopsied joints. Six synovial specimens were PD-positive (from 3 knees, 2 wrists and 1 elbow) while 5 synovial specimens were PD-negative (from 5 knees). In comparison with the PD-negative synovial specimens, the PD-positive synovial specimens had significantly more lymphocyte infiltration, vessel proliferation and lining hyperplasia on histologic examination. There was no significant difference in fibrin exudate and stromal fibrosis between the PD-positive and the PD-negative synovial specimens. PD signals in rheumatoid synovium indicate active inflammation and vascularization supported by synovial histopathology. Our study establishes the connection between synovial PD signals and active synovitis in RA.

BCOR-CCNB3-positive soft tissue sarcoma with round-cell and spindle-cell histology: a series of four cases highlighting the pitfall of mimicking poorly differentiated synovial sarcoma.

AIMS: BCOR-CCNB3 sarcoma is a genetically defined undifferentiated malignancy with Ewing sarcoma (ES)-like round cells, and preferentially affects the bones of male adolescents. Sarcomas harbouring BCOR-CCNB3 rarely arise from soft tissues; therefore, we aimed to report four cases to expand the clinicopathological spectrum. METHODS AND RESULTS: By reverse transcription polymerase chain reaction and confirmatory sequencing, we detected a BCOR-CCNB3 transcript in primary undifferentiated sarcomas of the deep musculature of four male patients, comprising two teenagers (aged 14 and 17 years) and two adults (aged 34 and 44 years). The tumours originated in the back (n = 2), pelvis (n = 1), and thigh (n = 1), and were 70-140 mm in size (mean, 107 mm). All tumours showed sheets of primitive round or ovoid cells with vesicular nuclei, active mitosis (28-41/10 high-power fields), variably prominent nucleoli, and geographical necrosis. This major component transformed into fascicles of elongated spindle cells with staghorn vessels and a myxoid reticular stroma, accounting for 10-50% of areas. All cases were positive for CD99, three were positive for TLE1, and one was positive for EMA, indicating poorly differentiated synovial sarcomas (PDSSs). Nuclear cyclin B3 reactivity was present in all cases, but not in molecularly confirmed atypical ESs and PDSSs. At the last follow-up (median, 13.5 months), one patient had died of lung metastasis, two were alive with tumours, and one was tumour-free. CONCLUSIONS: BCOR-CCNB3-positive sarcomas may primarily occur in soft tissues of adults and show PDSS-mimicking round-cell and spindle-cell histology with aggressive behaviour. Cyclin B3 is useful for selecting candidates for BCOR-CCNB3 molecular testing.