Search

// Jingxuan Wang 1 , Kun Gao 1 , Wanting Lei 1 , Lina Dong 1 , Qijia Xuan 1 , Meiyan Feng 2 , Jinlu Wang 1 , Xiangnan Ye 1 , Tuan Jin 1 , Zhongbai Zhang 3 , Qingyuan Zhang 1 1 Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medicial University, Harbin 150040, China 2 Department of Pathology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150040, China 3 Logistics University of People’s Armed Police Force, Tianjin 300162, China Correspondence to: Qingyuan Zhang, email: wjxilywendy@126.com Keywords: lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), diffuse large B-cell lymphoma (DLBCL), tumor-associated macrophages, programmed cell death-1 (PD-1) Received: April 27, 2016 Accepted: December 06, 2016 Published: December 27, 2016 ABSTRACT The research aims to examine the prognostic value of the lymphocyte-to-monocyte ratio (LMR), neutrophil-to- lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in diffuse large B-cell lymphoma (DLBCL). The relation of these hematologic indicators to poor antitumor immunity and prognosis must be investigated. Clinicopathologic data and survival information of 355 patients with DLBCL was retrospectively analyzed. Univariate analysis revealed that lower LMR (

Tumor-infiltrating lymphocytes (TILs) in primary melanomas are thought to represent the host antitumor immune response, but controversy exists over whether TILs offer independent prognostication of survival. We studied a cohort of 1241 patients with primary melanoma to assess the association of absent, nonbrisk, and brisk TIL grade with survival outcomes. We tested whether quantitative TIL counts using immunohistochemical lymphocyte markers CD3, CD45, and FOXP3 add prognostic value to TIL grading compared with histology alone in 15% of the cohort. To assess for intergroup immunologic heterogeneity among TIL grades, we investigated differential expression of 594 immunoregulatory genes in 67 primary melanomas. On histologic evaluation of 1241 primary melanomas, TILs were graded as absent (n=388, 31%), nonbrisk (n=330, 27%), and brisk (n=523, 42%). Patients with brisk TILs had improved recurrence-free survival (P=.025) and overall survival (P=.006) compared with patients with nonbrisk and absent TILs, for which there were no differences in recurrence-free survival (P=.40) or overall survival (P=.41). TIL quantitation by immunohistochemistry did not improve prognostication compared with TIL grading on hematoxylin and eosin-stained sections. Melanomas with nonbrisk and absent TILs share similar immunoregulatory gene expression profiles. In contrast, melanomas with brisk TILs demonstrate upregulation of T-cell activation pathways and inhibition of upstream immune checkpoint regulators. The presence of TILs in primary melanomas represents a heterogeneous group, and caution in prognostic interpretation is warranted. Melanomas with brisk TILs are defined by an immunostimulatory gene expression profile and improved prognosis compared with melanomas with nonbrisk or absent TILs.

Objective: IgG4-related disease (IgG4-RD) is an idiopathic inflammatory condition that causes pseudotumor formation in single or multiple organs, including those of the head and neck. Temporal bone involvement is rare, with only 3 cases of unilateral temporal bone IgG4-RD described in the literature. We report the first known case of IgG4-RD of bilateral temporal bones and describe its clinical presentation, diagnosis, and treatment. Methods: The patient was a 52-year-old man with latent tuberculosis (TB) who presented with a 10-year history of bilateral profound hearing loss and vestibular dysfunction. Computed tomography and magnetic resonance imaging demonstrated bilateral labyrinthine destruction with invasion of the posterior fossa. Results: Immunoglobulin level testing showed elevated total serum IgG levels with normal IgG4 levels. Bilateral mastoidectomies were performed, with biopsy samples demonstrating IgG4 staining with IgG4-positive plasma cells up to 40/HPF (high power field) on the right and 20/HPF on the left, consistent with bilateral IgG4-RD. Conclusion: IgG4-RD of bilateral temporal bones presents with chronic and progressive bilateral hearing loss and vestibular dysfunction. Clinical presentation and radiologic findings are nonspecific, and definitive diagnosis must be made with histopathology and immunostaining. Corticosteroids are therapeutic, but surgical resection may be necessary for temporal bone IgG4-RD to improve long-term remission.

We used the PathoScope platform to perform species level analyses of publicly available, 16S rRNA pyrosequenced, asymptomatic urine data to determine relationships between microbiomes, and clinical and functional phenotypes.We reanalyzed previously reported, cross-sectionally acquired urine samples from 47 asymptomatic subjects, including 23 controls and 24 subjects with neuropathic bladder. Urine was originally collected by the usual method of bladder drainage and analyzed by urinalysis, culture and pyrosequencing. Urinalysis and culture values were stratified as leukocyte esterase (0, or 1 or greater), nitrite (positive or negative), pyuria (fewer than 5, or 5 or greater white blood cells per high power field), cloudy urine (positive or negative) and urine culture bacterial growth (less than 50,000, or 50,000 or greater cfu/ml). PathoScope was used for next generation sequencing alignment, bacterial classification and microbial diversity characterization.Subjects with neuropathic bladder were significantly more likely to have positive leukocyte esterase and pyuria, cloudy urine and bacterial growth. Of 47 samples 23 showed bacterial growth on culture and in all samples bacteria were identified by pyrosequencing. Nonneuropathic bladder urine microbiomes included greater proportions of Lactobacillus crispatus in females and Staphylococcus haemolyticus in males. The Lactobacillus community differed significantly among females depending on bladder function. Irrespective of gender the subjects with neuropathic bladder had greater proportions of Enterococcus faecalis, Proteus mirabilis and Klebsiella pneumonia. In 4 subjects with neuropathic bladder Actinobaculum sp. was detected by sequencing and by PathoScope but not by cultivation and in all cases it was associated with pyuria.Using PathoScope plus 16S pyrosequencing we were able to identify unique, phenotype dependent, species level microbes. Novel findings included absent L. crispatus in the urine of females with neuropathic bladder and the presence of Actinobaculum only in subjects with neuropathic bladder.

Background and Aims In the International Consensus Diagnostic Criteria (ICDC), autoimmune pancreatitis (AIP) is classified into types 1 and 2, and its definite histopathology diagnosis can be made based only on surgical or core biopsy specimens. Although EUS-guided FNA (EUS-FNA) biopsy is a safe technique for the collection of pancreatic tissue, no consensus viewpoint has been reached with regard to the role of EUS-FNA biopsy in the diagnosis of AIP. This study investigated the utility of pancreatic tissue collected by EUS-FNA biopsy by using a standard 22-gauge aspiration needle in the diagnosis of AIP. Methods Patients with suspected AIP were prospectively enrolled in Nagoya University Hospital and Nagoya University–affiliated institutions. Pancreatic tissue was collected from each by EUS-FNA biopsy with a standard 22-gauge aspiration needle. Results Fifty patients were registered, including 45 with a final diagnosis of AIP. Lymphoplasmacytic infiltration and abundant immunoglobulin G 4 –positive plasmacyte infiltration (>10/high-power field) were detected in 36 (72%) and 27 (54%) patients, respectively. Obliterative phlebitis and storiform fibrosis were not detected in our study. Granulocytic epithelial lesions (GEL) were observed in 3 patients. The sensitivity, specificity, positive predictive value, and negative predictive value of EUS-FNA biopsy to definitively diagnose AIP were 7.9% (3/38), 100% (12/12), 100% (3/3), and 25.5% (12/47), respectively. Pathology evaluation of pancreatic tissue collected by EUS-FNA biopsy improved the diagnostic accuracy in 8 (16%) of the 50 patients. Conclusions In this study, EUS-FNA biopsy by using a standard 22-gauge aspiration needle is not an effective diagnostic method for most patients with AIP. The combination of level 2 histology diagnosis of AIP with other findings specified in the ICDC slightly improved the diagnostic accuracy, although it still remains insufficiently accurate for routine clinical use.(Clinical trial registration number: 000006297.)

Eosinophil-type nasal polyp (NP) is common in Western population. This aim of this study was to determine the histology type of NP among different Malaysian ethnic groups. A total of 122 chronic rhinosinusitis with nasal polyposis (CRSwNP) patients were retrospectively enrolled and demographic data was recorded. The histological slides were retrieved. The number of eosinophils and non-eosinophils were counted and average number of inflammatory cells for each high power field was calculated. Eosinophil-predominant was seen in 32.8% of patients and 67.2% was non-eosinophil-predominant. Phenotypes of NP significantly showed an association with ethnicity (x² = 8.322; p < 0.05). A total of 78.9% of Chinese nasal polyps showed non-eosinophil predominant, while Malay and Indian nasal polyps revealed 71.9% and 40.7% of non-eosinophilic phenotype, respectively. Our study showed that Malaysian population had a non-eosinophilic phenotype of nasal polyps. There was a significant association in Malaysian ethnicity with the highest percentage in Chinese population.

We report a case of immunoglobulin(Ig)G4-related disease with the radiologic and histopathological manifestations resembling usual interstitial pneumonia (UIP). The patient was a 62-year-old man who presented with progressive dyspnea of insidious onset. High resolution computed tomography of the chest showed lower-lobe predominant peripheral reticulation and traction bronchiectasis but no honeycomb change. Microscopic examination of the surgical lung biopsy showed characteristic features of UIP including architectural distortion by fibrosis with peripheral and paraseptal accentuation, scattered fibroblast foci and microscopic honeycomb change. In addition there were prominent multifocal lymphoplasmacytic infiltrates with a marked increase of IgG4-positive plasma cells (79 per high power field in hot spots) and high IgG4/IgG ratio (up to 67%). The serum IgG4 level was elevated at 760 mg/dl (reference range 9-89), with normal levels for the other IgG subclasses and negative serologic markers for autoimmune diseases. The patient’s symptoms improved significantly with oral corticosteroid treatment.

Phyllodes tumor (PT) of the breast is a rare disease usually presents as a large lump. The aim of this study was to report low grade malignant (borderline) PT of the breast in Kermanshah, Iran. A 55-year-old lady was admitted to the surgery ward with left breast mass since 2-3 months ago. In past medical history, the patient had left breast surgery due to fibrocystic change seven years ago. Grossly her specimen consisted in a piece of gray soft tissue measuring 10*8*4.5 cm with lobulated appearance and small cystic areas. In permanent diagnosis, the pathologist reported low-grade malignant (borderline) PT. Microscopically the tumor was composed of benign glandular elements and hypercellular spindle-shaped stroma. Mitotic index was 3/10 high power field (HPF). The border was well-circumscribed with satellite lesion. In conclusion, the diagnosis of borderline phyllodes tumor cannot be made only on age, the size of tumor, imaging or clinical features. Microscopic evaluation with evaluation of stromal cellularity, atypia, mitotic counts and border of the tumor is necessary for definite diagnosis and categorizing of this tumor.

MD Klinnert, D Atkins, Z Pan. J Pediatr Gastroenterol Nutr. 2019;69(6):682–689 To evaluate if children with eosinophilic esophagitis (EoE) demonstrated an association between health-related quality of life (HRQoL) improvements and symptom reduction during treatment of 1 year, to examine age-related EoE discrete symptom presentation, and to describe residual symptom and HRQoL burden. A prospective cohort of children and their families with established diagnosis of EoE based on previously identified criteria, including presence of upper intestinal symptoms, ≥15 eosinophils/high power field in the esophageal mucosa, treatment with proton pump inhibitors for 2 months before EoE diagnosis, and alternative causes for symptoms and eosinophilia ruled out; and new patients to tertiary care programs at …

IMPORTANCE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be documented in various tissues, but the frequency of cardiac involvement as well as possible consequences are unknown. OBJECTIVE: To evaluate the presence of SARS-CoV-2 in the myocardial tissue from autopsy cases and to document a possible cardiac response to that infection. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from consecutive autopsy cases from Germany between April 8 and April 18, 2020. All patients had tested positive for SARS-CoV-2 in pharyngeal swab tests. EXPOSURES: Patients who died of coronavirus disease 2019. MAIN OUTCOMES AND MEASURES: Incidence of SARS-CoV-2 positivity in cardiac tissue as well as CD3(+), CD45(+), and CD68(+) cells in the myocardium and gene expression of tumor necrosis growth factor α, interferon γ, chemokine ligand 5, as well as interleukin-6, -8, and -18. RESULTS: Cardiac tissue from 39 consecutive autopsy cases were included. The median (interquartile range) age of patients was 85 (78-89) years, and 23 (59.0%) were women. SARS-CoV-2 could be documented in 24 of 39 patients (61.5%). Viral load above 1000 copies per μg RNA could be documented in 16 of 39 patients (41.0%). A cytokine response panel consisting of 6 proinflammatory genes was increased in those 16 patients compared with 15 patients without any SARS-CoV-2 in the heart. Comparison of 15 patients without cardiac infection with 16 patients with more than 1000 copies revealed no inflammatory cell infiltrates or differences in leukocyte numbers per high power field. CONCLUSIONS AND RELEVANCE: In this analysis of autopsy cases, viral presence within the myocardium could be documented. While a response to this infection could be reported in cases with higher virus load vs no virus infection, this was not associated with an influx of inflammatory cells. Future investigations should focus on evaluating the long-term consequences of this cardiac involvement.

Introduction: Venetoclax is an oral inhibitor of the anti-apoptotic protein BCL-2, and is highly effective for the treatment of patients with chronic lymphocytic leukemia (CLL). Dependence of CLL cells on alternative anti-apoptotic proteins may result in intrinsic resistance to BCL-2 inhibition. The predictive and prognostic role of the expression of BCL-2 alternative proteins in CLL patients treated with venetoclax has not been yet explored. Methods: Patients with CLL treated with single agent venetoclax at MD Anderson Cancer Center between 05/2012 and 01/2016, and with available pre-treatment bone marrow samples, were included in the study. All samples were analyzed by immunohistochemistry (IHC) for BCL-W, BCL-XL, BCL2-A1 and MCL-1, and >1 positive CLL cells per high power field (40X) was considered positive. Response was assessed according to 2008 iwCLL guidelines, using the clinical and imaging criteria. Results: Twenty-seven patients were included in the study: 74.1% were male, 50% aged > 65 years, and 63% had Rai stage III-IV; 26% had mutated IGHV, 48% had del17p/del11q by FISH, and 40% had a complex karyotype by metaphase cytogenetics; 96% had been previously treated, 37% with a BTK inhibitor. Overall, 15% had pre-treatment bone marrow samples positive for BCL-W, and 7% for BCL-2A1 (Figure), while none of the samples was positive for BCL-XL or MCL-1. Overall response rate was 93%, and 14 (52%) patients achieved CR. A higher CR rate was observed in patients with positive BCL-W (75% vs 48%, p=0.60), positive BCL-2A1 (100% vs 48%, p=0.60), and double positive patients (80% vs 45%, p=0.33), though not statistically significant After a median follow-up of 50 months (95%CI, 46-54 months), 13 (48%) patients progressed, and median progression-free survival (PFS) was 51 months (95% CI, 27-75 months). A longer median PFS was observed for patients with positive BCL-W (not reached [NR] vs 36 months, p=0.46), positive BCL-2A1 (NR vs 35 months, p=0.29), and double positive patients (NR vs 36 months, p=0.20)(Figure 2), though not statistically significant. At most recent follow-up, 9 (33%) patients died, all of progressive disease, and median overall survival (OS) was 65 months (range, 2-65 months). A longer median OS was observed for patients with positive BCL-W (NR vs 65 months, p=0.19), positive BCL-2A1 (NR vs 65 months, p=0.36), and double positive patients (NR vs 65 months, p=0.12) (Figure), though not statistically significant. Conclusion: Pre-treatment expression of BCL-2 alternative proteins by IHC does not predict response to venetoclax in patients with CLL. More sensitive techniques, such as gene expression profiling and BH3 profiling, are needed to explore the predictive role of alternative anti-apoptotic pathways in these patients. Dependence on alternative BCL-2 proteins may associate with a better outcome for CLL patients, and larger dataset are needed to confirm this finding. Citation Format: Fateeha Furqan, Ellen J. Schlette, Francisco Vega, Ignacio I. Wistuba, Luisa M. Soto, Mario L. Piubelli, William G. Wierda, Alessandra Ferrajoli, Paolo Strati. Expression of BCL2 alternative proteins and association with outcome in CLL patients with venetoclax [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 801.

Background Immune checkpoint inhibitors (ICIs) are the standard treatment for non-small cell lung cancer. The unique adverse events that can arise after treatment with ICIs are known as immune-related adverse events (irAE). As the number of cases under treatment with ICIs increases, new types of characteristics of irAE have emerged. This case report suggests that IgG4-related pleural disease could occur as an irAE. Case presentation A 64-year-old man was diagnosed with pulmonary adenocarcinoma stage IIIB. Following concurrent chemoradiotherapy, durvalumab was administered every two weeks. The patient complained of dyspnea on effort 4 months after the initiation of durvalumab therapy. Chest CT scans showed mild bilateral pleural effusion 4 months after the initiation of durvalumab therapy, and the amount of pleural effusion increased further at 7 months. Durvalumab was thought to be a potential cause of pleural effusion and was withdrawn after 13 courses of administration over 7 months. The level of serum IgG4 was 2750 mg/dL. The levels of IgG4 of the pleural fluids were 2790 mg/dL on the right side and 2890 mg/dL on the left side at 7 months. Microscopic examination of the pleural biopsy revealed lymphoplasmacytic infiltration with storiform fibrosis. Immunohistochemical examinations showed that the number of IgG4-positive cells was > 20/high power field and the percentage of IgG4-positive to IgG-positive plasma cells was > 50%. Oral prednisolone at a dose of 30 mg/day was initiated, and remarkable clinical improvements were achieved. After 4 months of prednisolone therapy, the level of serum IgG4 decreased to 370 mg/dL and chest CT revealed the disappearance of bilateral pleural effusion. Conclusion This was a case of IgG4-related pleural disease in a patient with pulmonary adenocarcinoma under durvalumab treatment. To our knowledge, this is the first case report of IgG4-related pleural disease as an irAE. It is important to consider the possibility of IgG4-related pleural disease in cases of pleural effusion during the treatment with ICIs.

Case Answer A 15-year-old woman presented to a hospital with malaise and visible pallor that had lasted for 2 weeks. The patient was treated with ferrous iron and discharged home. Following discharge, the patient’s symptoms did not improve and she subsequently developed dark urine. As a result, the family decided to seek care at a larger center. When the patient arrived to our center, urinalysis was obtained in view of the reported symptoms. Dipstick urinalysis revealed pH 7.0, specific gravity 1.015, protein 3+, hemoglobin 3+, urobilinogen excess, and bilirubin 1+. Examination of the spun urine sediment revealed numerous renal tubular epithelial cells (RTECs) (>50/high power field), red blood cells (1–2/high …

A 60-year-old woman was referred to our clinic with a diagnosis of vitritis in both eyes (BE) that had been treated with oral steroids for more than 1 month. Visual acuity of BE was counting fingers close to face. Examination revealed 10–15 cells/high power field in the anterior chamber of BE

IgG4-related disease is characterized by lymphoplasmacytic inflammation and fibrosis, often leading to mass-forming lesions in different organs. When IgG4-related disease affects the bile ducts, it is called IgG4-related sclerosing cholangitis. A 74-year-old male complained of dysphagia and abdominal pain. Endoscopic retrograde cholangiography and magnetic resonance cholangiography revealed bile duct changes suspicious of a bile duct carcinoma or cholangitis. Liver biopsy showed storiform fibrosis, lymphoplasmacytic infiltration, obliterative phlebitis, and a portal-based inflammatory nodule with expansion of a portal tract. Hot spots revealed 339 IgG4-positive cells per high power field (HPF) and an IgG4/IgG ratio of 72%. Eight months earlier, an inguinal lymph node had been removed, showing expanded interfollicular zones and increased plasma cells. Hot spots revealed 593 IgG4-positive cells and an IgG4/IgG ratio of 92%. The serum IgG4 of the patient was elevated nearly 10 times upper limit of normal. The diagnosis of IgG4-related sclerosing cholangitis associated with IgG4-related lymphadenopathy was made. There was good response to treatment with prednisolone and azathioprine. The differentiation of IgG4-related sclerosing cholangitis from primary sclerosing cholangitis and bile duct carcinoma is often difficult. Liver biopsy only rarely contributes to this setting, but we describe and report in detail a case where liver biopsy showed a portal-based inflammatory nodule with the characteristic features of this disease.

CONTEXT: Tumor budding (TBud) is recognized as a poor prognostic marker in colorectal cancer (CRC) with important treatment implications in Stage II cancers and malignant polyps. There are multiple propositions for bud count reporting but without an uniformly accepted system. The International TBud consensus conference (ITBCC) proposed mandatory reporting of budding on the single worst ×20 high power field (0.785 mm2 area) with a 3-tier scoring system (low/intermediate/high for 0–4, 5–9, and ≥10 buds/×20 field). AIMS: Due to the lack of availability of ×20 objective, we aimed to validate a simple ×40 field count (0.236 mm2 area) for wider applicability. METHODS: Bud count was done on hematoxylin and eosin-stained slides of 92 archived cases of colon cancer on the worst ×20 and ×40 fields (0.95 mm2 and 0.236 mm2 area) (hotspot method). Count for 0.785 mm2 area was calculated using ITBCC normalization factor of 1.2. Interobserver variability between two observers was assessed. Score groups for ×20 field and proposed score groups for 40× field (low/intermediate/high for 0–1, 2–4 and ≥5 buds) were compared with disease-free survival. RESULTS: High bud score was seen in 20.6% and 31.5% cases, respectively, using the ×20 and ×40 methods. High interobserver concordance was noted (ICC 0.95). Both the ITBCC bud score and our proposed 40× scoring correlated significantly with prognosis (P = 0.030, log-rank test). CONCLUSIONS: In centers lacking 20× objective, we propose using the worst 40× hotspot method for reporting of budding for all CRCs as a simple, reproducible and prognostically significant scoring system.

Isolated microscopic hematuria is a condition characterized by the presence in the urine of an “abnormal” number of erythrocytes in the absence of proteinuria. Several studies have been published on this condition, but with heterogeneous inclusion criteria and variable outcomes at follow-up. In this retrospective study, we describe a selected and homogenous cohort of patients who presented with isolated microscopic hematuria of glomerular origin. We included in the study patients with isolated microscopic hematuria of glomerular origin (> 1 erythrocyte/high power field at 400× and ≥ 40% dysmorphic erythrocytes and/or ≥ 5% acanthocytes and proteinuria ≤ 150 mg/24 h) with a follow-up of > 60 months from the first documentation of microscopic hematuria. Forty-two patients (M 12, F 30, age at presentation 14–68 years, eGFR

Background/aims Esophageal eosinophilia occurs in many conditions, including eosinophilic esophagitis (EoE) and proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE), which have been increasingly recognized in Western countries. There have been only a few reports in Korea. Here, we evaluated the clinical and endoscopic characteristics of patients with esophageal eosinophilia from our experience. Methods Nineteen patients were diagnosed with esophageal eosinophilia based on typical symptoms, endoscopic features, esophageal eosinophilia with ≥15 eosinophils/high power field, and response to medication by PPI. Symptoms, endoscopic and pathological findings were evaluated. Results Of the 19 patients, 2 patients were diagnosed with EoE, 7 patients were diagnosed with PPI-REE, and 10 patients were undetermined due to loss to follow-up. Among these 19 patients, dysphagia was present in 11, and heartburn, dyspepsia and refluxin 8. Sixteen patients had common endoscopic features, such as longitudinal furrows, concentric rings, strictures, and white plaques; however, 3 patients had normal findings. Nine patients underwent endoscopy at the time of follow-up. Two patients had complete resolution, and 3 had partial resolution. However, 4 patients showed no endoscopic changes. All patients showed symptom improvements. Conclusions The clinical and endoscopic characteristics of both groups in Korea were undistinguishable. However, after treatment, endoscopic findings were different between the two groups. Large-scale studies are warranted to confirm our findings.

Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE. We performed a multicenter, double-blind trial of 99 adults with active EoE randomly assigned (1:1:1) to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, from September 2014 through December 2015. Patients were seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. Patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation. At week 16, mean changes in esophageal eosinophil count per hpf were a reduction of 94.8 ± 67.3 in patients who received 180 mg RPC4046 (P < .0001) and a reduction of 99.9 ± 79.5 in patients who received 360 mg RPC4046 (P < .0001) compared with a reduction of 4.4 ± 59.9 in patients who received placebo. The 360-mg RPC4046 group, compared with the placebo group, showed significant reductions in validated endoscopic severity score at all esophageal locations (P < .0001), validated histologic grade and stage scores (both P < .0001), and clinician's global assessment of disease severity (P = .0352); they had a numerical reduction in scores from the dysphagia symptom diary (P = .0733). Significant reductions in esophageal eosinophil counts and histologic and endoscopic features were observed in patients with steroid-refractory EoE who received RPC4046. The most common adverse events were headache and upper respiratory tract infection. In a phase 2 trial of patients with EoE, we found RPC4046 (a monoclonal antibody against IL13) to reduce histologic and endoscopic features compared with placebo. RPC4046 was well tolerated. ClinicalTrials.gov no: NCT02098473.

Tumor budding is defined as the presence of single tumor cells or small tumor clusters (less than five cells) that ‘bud’ from the invasive front of the main tumor. Tumor budding (TB) has recently emerged as an important adverse prognostic factor for many different cancer types. In colorectal carcinoma (CRC), tumor budding has been independently associated with lymph node metastasis and poor outcome. Pathologic assessment of tumor budding by light microscopy requires close evaluation of tumor invasive front on intermediate to high power magnification, entailing locating the ‘hotspot’ of tumor budding, counting all TB in one high power field, and generating a tumor budding score. By automating these time-consuming tasks, computer-assisted image analysis tools can be helpful for daily pathology practice, since tumor budding reporting is now recommended on select cases. In this paper, we report our work on the development of a tumor budding detection system in CRC from whole-slide Cytokeratin AE1/3 images, based on de novo computer algorithm that automates morphometric analysis of tumor budding.

Background: The outcome of primary sclerosing cholangitis (PSC) after liver transplantation can be affected by recurrent PSC (rPSC) and subsequent graft failure. IgG4-related sclerosing disease is a recently described entity that has a similar morphological appearance to PSC, making the distinction difficult. However, IgG4-related sclerosing cholangitis has an excellent prognosis since it is steroid sensitive, but the impact of IgG4 on rPSC after liver transplant is still unknown. Objectives: To determine the association between IgG4 positive immunochemical staining in liver explants and recurrence of primary sclerosing cholangitis post-liver transplantation. Methods: Clinical information on all adult patients who underwent liver transplantation for PSC from 1990 to 2014 at our institution was obtained. IgG4 immunochemical staining was performed on the porta-hepatis region of these patient’s explanted livers. Immunochemical staining was considered to be positive if the score was > 5 cells/high power field (HPF). Results: Eighty patients met inclusion criteria. IgG4 staining was positive in 21 subjects. Median time for follow-up in the IgG4 positive group was 99.6 months compared to 152.6 months in the IgG4 negative. There were more instances of rPSC in the IgG4 negative group compared to the IgG4 positive group (26% vs. 5%, P < 0.009), and rPSC occurred earlier in the IgG4 negative group (P = 0.016). The frequency of graft failure, however was not significantly different among the two groups. Conclusions: The presence of IgG4 positive cells in liver explants of patient’s transplanted for PSC is associated with fewer episodes of and longer time to recurrent PSC. In addition, IgG4 status of the liver explants does not affect graft survival. Presence of IgG4 positive cells may suggest protective effect against recurrence of PSC.

Introduction The incidence of eosinophilic oesophagitis (EoE) is increasing. Following diagnosis, the initial therapy is to place patients on protein pump inhibitors (PPI) and repeat oesophageal biopsies, as 30% of patients will be PPI responsive. As acid reflux is known to cause eosinophilic oesophagitis, pH impedance and manometry is also carried out to aid management. This is usually carried out as a separate hospital visit. An alternative test is wireless pH monitoring with a BRAVO device during which a pH monitoring chip is attached to the distal oesophagus at the same time as a gastroscopy. This is also an opportunity to take the repeated biopsies to assess PPI response; pH monitoring could therefore be integrated into the repeated endoscopic pathway and avoid the extra appointment for standard pH impedance. The fragile ‘crepe-paper’ mucosa of EoE has been raised as a potential source of early detachment of BRAVO capsules thereby limiting their use in this condition. Aim To assess whether there is any difference in the detachment day of the BRAVO capsule in patients with EoE when compared to other conditions and thereby determine its use in the pathway for the investigation of EoE patients. Method The electronic records of patients with EoE who also had a BRAVO were examined retrospectively between June 2008 and January 2018 at a single centre. The total time of recording of the BRAVO capsule was noted and whether reflux was significant. In addition the number of eosinophils per high power field on the oesophageal biopsies taken prior to or at the same time as the BRAVO study was recorded. Results Ten patients with EoE underwent 12 BRAVO studies (M: F 1:1, age range 18–56). One study detached within one day, three after two days and eight after four days. The patient whose capsule detached early went on to have a second BRAVO study lasting 4 days. Detachment times were compared to those for non-EoE in our department for a single calendar year (December 2016-December 2017). There was no significant difference in detachment rates between these two groups (p Conclusion Bravo pH manometry is a useful investigation in patients with EoE and beneficial to the patient; reducing the number of invasive procedures by allowing the attachment of the BRAVO capsule at the same time as taking post-PPI biopsies. The detachment was not significantly greater in patients with EoE although the numbers are small. There was no correlation between eosinophil count per HPF and attachment times. The only drawback is that patients are expected to stop PPI 7 days prior to the BRAVO being placed with a theoretical risk of a recrudescence of oesophageal eosinophilia in that time although the standard time for redevelopment of EoE is around 6–8 weeks.

Neutrophils may be involved in the local pathophysiology of chronic graft-versus-host disease (cGVHD). We evaluated neutrophil infiltration in cGVHD using conjunctival impression cytology (IC) and its clinical correlation with ocular surface status and neutrophil enzyme levels in tears.This cross-sectional observational study included 76 patients with cGVHD. The ocular surface was assessed for the tear break-up time, Schirmer I test, corneal and conjunctival staining score, meiboscore, and the ocular surface disease index questionnaire. Conjunctival IC was performed at the temporal, superior bulbar, and upper palpebral conjunctiva, and the number of neutrophils (cells/high power field [HPF]) was calculated. Neutrophil elastase (NE), myeloperoxidase (MPO), and matrix metalloperoxidase-8 and -9 levels in tear washes were measured in 20 patients.The number of neutrophils was significantly greater at the upper palpebral conjunctiva (median [range], 16.5 [0 to 147] cells/HPF) than at the temporal and superior bulbar conjunctiva (0 [0 to 70] and 0 [0 to 105] cells/HPF; P 0.0001). The number of neutrophils at the upper palpebral conjunctiva showed moderate correlations with the corneal staining score and the NE and MPO levels in tears (r = 0.668, 0.553, and 0.563, respectively; P 0.0001, P = 0.014, and 0.012).Our results suggest that neutrophils at the upper palpebral conjunctiva associate with the clinical manifestations and inflammatory status of the ocular surface in cGVHD. Conjunctival neutrophils should be addressed when assessing the inflammatory activity of ocular cGVHD and exploring its pathogenesis.

Background Urticarial vasculitis (UV) is a clinicopathologic entity in which skin lesions resemble urticaria clinically but last more than 24 hours and resolve with residual purpura. In this study, we evaluated distinguishing histological features of UV from common urticaria to differentiate between these two entities. Methods During 1 year, 55 urticaria and 245 UV samples were assessed. The selection criteria for UV included: (1) samples that the histological diagnosis was confirmed by two independent dermatopathologists, (2) the histological diagnosis of UV was inconsistent with the first clinical impression and lesion characteristics. Results Of our 245 UV patients, 96% had endothelial swelling, 18% had red blood cell (RBC) extravasation, neutrophilic infiltration was seen in 46.7%, and perivascular, interstitial, and perineural eosinophilic infiltration in 198 (81.8%), 181 (74.2%), and 118 (48.1%), respectively. Among different histological findings, endothelial cell swelling as well as neutrophil around vessels and eosinophilic infiltrations were statistically different between two groups (P-value ˂ 0.001). Both urticaria and UV samples showed a predominantly lymphocytic infiltration more than 10 cells per high power field (HPF) (98.2% of urticaria, 98.8% of UV), and only two patients (0.8%) with UV had predominant neutrophilic infiltration (more than 10 cells/HPF). Conclusion We have found that both urticaria and UV showed a predominantly lymphocytic infiltration along with RBC extravasation, endothelial cell swelling, and fibrin deposition in UV. Moreover, significant perineural, perivascular, and interstitial infiltration of eosinophil in UV lesions compared to urticaria was another point that indicates special contribution of these cells in UV pathogenesis.

Background and Aims Endoscopic resection has been performed for treatment of GI stromal tumors (GISTs) in the upper GI tract. However, the therapeutic roles of the endoscopic procedure remain debatable. We aimed in this retrospective study to evaluate the feasibility and long-term follow-up results of endoscopic resection of GISTs in the upper GI tract, compared with surgery. Methods Between March 2005 and August 2014, 130 cases of GIST in the upper GI tract were resected. We compared baseline characteristics and clinical outcomes including R0 resection rate and recurrence rate between the endoscopy group (n = 90) and surgery group (n = 40). Results The most common location of GIST was the stomach body in the endoscopy group, whereas it was the duodenum in the surgery group ( P = .001). Tumor size was significantly smaller (2.3 vs 5.1 cm; P P P P = .001), and 50.0% of resected tumors belonged to a very low–risk group in the endoscopy group, whereas 35.0% and 30.0% belonged to low-risk and high-risk in the surgery group ( P = .001). However, during 45.5 months of follow-up, the recurrence rate was not significantly different between the 2 groups (2.2% vs 5.0%; P = .586). Conclusions Endoscopic resection might be an alternative therapeutic modality for GISTs in the upper GI tract in selective cases.

Background: Solitary fibrous tumors of the pleura (SFTP) are rare neoplasms with unpredictable behavior. Lack of unifying criteria for benign or malignant SFTP has resulted in reports of SFTP exhibiting malignant behavior years after complete surgical resection (despite benign initial diagnosis). Additionally, the role of trans-thoracic needle biopsy in initial management of SFTP is unclear. Understanding predictors of malignancy identifies patients at unacceptably high risk for non-surgical primary therapy, and for recurrence despite complete surgical resection. Objectives: The primary objectives were to identify clinicopathological predictors of malignancy & recurrence in SFTP. The secondary aim was to determine the role of trans-thoracic needle biopsy in the management decision algorithm of SFTP. Methods: Retrospective chart review was conducted (Jan. 1983-Dec. 2013) at the Ottawa Hospital for pathologically confirmed SFTP. Data were collected on biopsy-related, clinical, histopathological & immunohistochemistry (IHC) variables. Appropriate tests of statistical inference were conducted for all variables. Results: Pathologically confirmed SFTP was identified in 26 cases. Transthoracic needle biopsy was conducted in 22 (84.6%); with 16 (72.7%) biopsies diagnostic of SFTP with IHC; 3 (13.6%) being malignant. Primary management was surveillance in 3 and complete surgical resection in 23. Surgical pathology reported 15 (65.2%) benign and 8 (34.8%) malignant cases. Local recurrence occurred in 3 and distant recurrence in 1. Initial pathology was benign in 3 (75%) with recurrence. Clinicopathologic variables analyzed did not predict recurrent disease. IHC features did not differ between malignant & benign pathology significantly. Predictors of malignant pathology included: infiltrative cellular pattern (p = 0.042), nuclear crowding (p = 0.006), tumour necrosis (p 4 mitoses/ 10 high power field (p < 0.003). Conclusion: Because numerous variables analyzed did not predict recurrent disease, long-term follow-up is warranted regardless of benign or malignant initial histology. Histologic not IHC features predicted malignant pathology. Trans-thoracic needle biopsy did identify malignant SFTP; however its main use should be to differentiate SFTP from other pleural neoplasms using IHC.

Background: Mitotic count is the most commonly used method of assessing the proliferative activity of a tumor. It is usually done in routine Hematoxylin & Eosin stained sections and is used for classification, grading, prognostication of tumors and sometimes as a decision factor for treatment. There are numerous variables that can influence the mitotic count like delay in fixation, thickness of the section, size of the high power field of the microscopes and so on. This study is designed to assess the relative importance of Intra-observer variability and Inter-observer variability on mitotic counting by keeping all different procedural factors constant. Methods: Sections from forty cases of breast cancer and twenty cases of high grade lymphoma formed the study material. Mitotic counts done by the principal investigator under standard conditions were compared with counts done by another experienced observer under standard conditions to evaluate the inter-observer variability. The principal investigator will make all counts twice at intervals of one month to assess intra-observer variability. Paired t test and linear regression were the statistical tests used in analysis. Ki-67 immunohistochemistry was also done in sections fixed at different intervals. Results: Our study showed that inter-observer (p=0.261) and intra-observer variation (p=0.261) is not statistically significant. In case of inter-observer variability the correlation is weak and not significant. Conclusions: Reproducibility in mitotic counting can be achieved by following a strict morphological criteria as well as a strict counting protocol.

OBJECTIVES The objective of this study was to determine the risk factors that may contribute to the diagnosis of microscopic hematuria (MH) in women. METHODS This multicenter case-control study reviewed cases of women presenting to Female Pelvic Medicine & Reconstructive Surgery sites with MH from 2010 to 2014. Microscopic hematuria was defined as 3 or more red blood cells per high power field in the absence of infection as indicated in the American Urologic Association guidelines. Controls were matched to cases in a 1:1 ratio and chart review of 10 risk factors was performed (urethral caruncle, pelvic organ prolapse, vaginal atrophy, personal or family history of nephrolithiasis, prior prolapse or incontinence surgery, past or current smoking, chemical exposure, family history of urologic malignancy, prior pelvic radiation, and prior alkylating chemotherapy). Odds ratios were performed to assess risk factors. RESULTS There were 493 cases and 501 controls from 8 Female Pelvic Medicine & Reconstructive Surgery sites. Current smoking, a history of pelvic radiation, and a history of nephrolithiasis were all significant risk factors for MH (P < 0.05). Vaginal atrophy, menopausal status, and use of estrogen were not found to be risk factors for MH (P = 0.42, 0.83, and 0.80, respectively). When stratifying the quantity of MH, women with increased red blood cells per high power field were more likely to have significant findings on their imaging results. CONCLUSIONS Our findings suggest that the risk factors for MH in women are current smoking, a history of pelvic radiation, and a history of nephrolithiasis.

Merkel cell carcinoma (MCC) is a rare skin malignancy associated with sun exposure and considered as a Neuroendocrine Tumor due to its characteristic histologic features. However there is increasing number of reports of Unknown Primary MCC's (UPMCC). Although initially UPMCC was considered a variant of known primary MCC, there is growing evidence that it could represent a different clinical entity. We present the case of a 60 year-old male patient who was referred to our department for surgical management of lymph node disease for UPMCC. The patient had undergone excisional biopsy of an inguinal lump, which was found to be an infiltrated lymph node by MCC. The patient underwent full imaging staging including a PET/CT, which failed to identify a primary site, and revealed only intra-abdominal lymph node disease. The patient underwent extended retroperitoneal and inguinal lymph node dissection and remains free of recurrence 16 months postoperatively., Highlights • Unknown Primary Merkel cell carcinoma is a rare NET, which usually presents with extensive lymph node involvement. • This tumor follows a more indolent natural course than a Merkel cell carcinoma of known primary and of similar staging. • Surgical excision with R0 resection remains a common practice in the management of unknown primary Merkel cell carcinoma. • Adjuvant chemotherapy after R0 resection is the usual practice, despite the lack of good quality literature evidence.

Herein, we report a complicated case of acute T-cell-mediated rejection (ACR) accompanied by C4d-negative acute antibody-mediated rejection (AMR) and cell debris in tubulus. A 32 year-old male was admitted for an episode biopsy with a serum creatinine (S-Cr) level of 1.83 mg/dL and pyuria (20-29 white blood cells per high power field) 49 days following kidney transplantation. Histological features included three distinct entities, mainly, in one of the three specimens: 1) focal aggressive tubulointerstitial inflammatory cell infiltration with moderate tubulitis, 2) inflammatory cell infiltration in peritubular capillaries (including neutrophils) and glomerular capillaries, and 3) cell debris consisting mainly of neutrophils in tubulus. Laboratory examination revealed evidence of non-human leukocyte antigen donor-specific antibodies. However, urinary culture and gram staining were negative. Considering both the histological and laboratory findings, the patient was diagnosed with ACR accompanied by C4d-negative AMR and suspicion of a urinary tract infection (UTI). The patient was treated for three consecutive days with steroid pulse therapy. The patient's S-Cr level decreased to ~1.5 mg/dL following treatment and did not increase thereafter. A second biopsy 133 days following kidney transplantation showed an excellent response to treatment and revealed no evidence of rejection. This case report demonstrates the difficulty in the diagnosis of, and therapy for, the complicated pathological findings of ACR, AMR and suspicion of a UTI.

Objectives To investigate the prognostic value of preoperative pyuria in patients with non-muscle-invasive bladder cancer. Methods We retrospectively reviewed data from 237 patients diagnosed with non-muscle-invasive bladder cancer. Pyuria was defined as urine containing ≥5 white blood cells per high power field. The association between clinicopathological factors and recurrence was assessed by Cox univariate and multivariate analyses. Results Preoperative pyuria was found in 116 (49.0%) patients. Pyuria was significantly associated with advanced age, positive cytology, multiple tumors, large tumor size, non-papillary tumors, T1 tumors and high-grade tumors. In univariate analysis of the entire patient population, pyuria, positive urine cytology, multiple tumors, pT1 tumors and no bacillus Calmette–Guerin were significantly associated with recurrence. Multivariate analysis showed that pyuria was an independent predictor of recurrence (hazard ratio 3.332, 95% confidence interval 2.052–5.410; P

The aim of this study was to ascertain if (1) the stage of reproductive cycle influences cytological results, (2) cytology obtained from an endometrial biopsy is more accurate than cytology derived using the cytobrush, and (3) different methods used for evaluation of cytological samples produce similar diagnostic results. Material was collected from 46 mares in estrus, 48 in diestrus and from 33 mares in anestrus. Smears were evaluated using two criteria. In criterion I, a total of 300cells were counted and the percentage of polymorphonuclear cells was recorded. In criterion II, the number of polymorphonuclear cells/high power field was determined. Endometrial biopsy samples were also examined histologically, and comparisons were made between cytological and histological results. Regardless of the method used for sample collection, endometritis was diagnosed significantly more frequently if smears were evaluated according to criterion I. The agreement between the number of polymorphonuclear cells infiltrated into the endometrial luminal epithelium and stratum compactum and the cytology results for smears evaluated according to criterion I was fair for anestrous mares, poor for diestrous mares, and moderate for mares in estrus. When cytological smears were evaluated according to criterion II the agreement between the histological and cytological and results was always poor. In summary, cytological evaluation of the mare endometrium should be based on counting the numbers of polymorphonuclear cells in relation to epithelial cells rather than counting the number of polymorphonuclear cells in relation to high power field.

Objective: to investigate the presence of eosinophils in oral intraepithelial neoplasia (OIN) and oral squamous cell carcinoma (OSCC) lesions and its relation to invasion. Subjects and methods: ninety‐nine oral biopsies were selected and subdivided into the following: OIN‐1(16 cases), OIN‐2 (18 cases), OIN‐3 (17 cases), microinvasive OSCC (10 cases), non‐metastatic OSCC (22 cases) and metastatic OSCC (16 cases). The tissue eosinophilia was evaluated histologically in slices stained with haematoxylin and eosin. Results: Eosinophil distribution was associated with diagnosis severity (p < .01). A significant difference was found between OIN‐3 or microinvasive OSCC and non‐metastatic or metastatic OSCC. Stromal invasion threshold was 7 eos/10 high power field (hpf) (96.1% specificity and 62.5% sensitivity). Eosinophils were absent in OIN‐1; in OIN‐2, two cases were positive. In OIN‐3, five cases showed tissue eosinophilia, four of which had ≥3 eos/hpf or ≥7 eos/10 hpf. Three cases were suspected of invasion; two had a previous history of OSCC with elevated eosinophil infiltrate. In microinvasive OSCC, the four positive cases presented ≥3 eos/hpf and ≥7 eos/10 hpf. Although not significantly different, non‐metastatic invasive OSCC had a higher number of cases (68.2%) with ≥22 eos/10 hpf contrasting with 50% in metastatic OSCC. Conclusion: our results suggest that eosinophils can be considered an indicator of invasion in OIN, helping in cases of difficult diagnosis. info:eu-repo/semantics/publishedVersion

Background and study aims Characteristic endoscopic findings, such as linear furrows, rings, and whitish exudates, indicate the presence of esophageal eosinophilia (EE), though no specific findings are known to distinguish eosinophilic esophagitis (EoE) from proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE). Here, we present a novel endoscopic finding in some EE patients possessing a linear longitudinal arrangement of whitish nodules with the appearance of the back of an Ankylosaurus dinosaur, termed Ankylosaurus back sign (ABS), and evaluations of its significance in affected patients. Patients and methods Fifty-five patients diagnosed with EE (≥ 15 eosinophils/high power field) who were treated at our hospital and shown to evaluate a PPI response were enrolled. Endoscopic findings at baseline and clinical parameters were retrospectively reviewed. Furthermore, the clinicopathological features of patients with ABS, as well as the relationship between its presence and PPI response were evaluated. Results Fifty-five patients (47 males, 8 females) with EE (17 with EoE, 38 with PPI-REE) were evaluated, of whom 50 (90.9 %) had linear furrows, the most frequently found feature, while ABS was found in 9 (16.4 %). Inter-observer agreement was substantial for ABS (κ 0.77). Interestingly, all patients with ABS had PPI-REE. Our findings revealed that the presence of ABS was closely associated with reflux esophagitis (RE) in patients with PPI-REE. Conclusions Although ABS was less frequent than typical endoscopic findings such as linear furrows in EE, this novel finding was closely associated with PPI-REE accompanied with RE. The clinical implications of ABS in patients with EE should be investigated further.

Besides the initial description of IgG4-related pancreatic disease, other sites are now commonly involved. However, occurrence of IgG4-related disease is rare in organ transplanted patients. A 57-year-old man who received a kidney transplantation presented with recurrent dyspnea on exertion. A computed tomography scan of the chest revealed bilateral interlobular septal thickening and multiple tubular and branching small nodular lesions in the right upper lobe, and mass-like consolidation of the left middle lobe. Despite no elevation of serum IgG4 level, a percutaneous core needle biopsy on consolidative mass showed interstitial fibrosis and infiltration of IgG4-positive plasma cells to be more than > 20 per high power field. After treatment with glucocorticoids and rituximab, the consolidative mass of the left middle lobe disappeared.

Objectives To evaluate the importance of leukocyturia in detecting the transition from asymptomatic bacteriuria to symptomatic infection in women with recurrent urinary tract infections. Methods In this cross-sectional study, we evaluated all women with recurrent urinary tract infection and asymptomatic bacteriuria who had been enrolled in two previous studies. Data from urological visits, urine analyses and microbiological evaluations were collected. Patients were divided into two groups: patients with symptomatic recurrence (group A) and patients without recurrence (group B), with a mean follow-up period of 38.8 months. Data on leukocyturia and clinical data were compared. Logistic regression analyses were carried out and areas under the receiver operating characteristic curves were calculated. Results A total of 301 women with symptomatic urinary tract infection were included in group A, whereas 249 women without clinical infection were included in group B. Group A showed a higher level of leukocytes in the urinary analysis taken at the moment of recurrence when compared with the baseline value (mean leukocytes per high power field 54 ± 5 vs 19 ± 6 at baseline; P 150% from baseline was used for logistic regression, the area under the receiver operating characteristic of the model was 0.82 (95% CI 0.78-0.94; P = 0.01). An increase of leukocytes/mm3 of >150% from baseline had a sensitivity of 90.1% and a specificity of 91.2% for symptomatic urinary tract infection. Conclusions This study shows that an increase of leukocyturia of >150% from baseline has a predictive role for the transition from asymptomatic bacteriuria to symptomatic urinary tract infection in women with recurrent urinary tract infections.

Objective.To identify patients presenting with isolated hematuria and/or pyuria in the absence of other systemic lupus erythematosus (SLE) disease activity, describe their demographics, and determine whether they present with evidence of SLE flare in a period adjacent to the presentation.Methods.We studied patients followed at the University of Toronto Lupus Clinic between 1970 and 2012. An episode of isolated hematuria (> 5 red blood cells per high power field) and/or pyuria (> 5 white blood cells per high power field) was defined as 2 consecutive visits with these findings in the absence of other concurrent SLE manifestations such as proteinuria, casts, or azotemia. We then excluded patients whose findings might be explained by urinary tract infections, menstruation, urolithiasis, and/or anticoagulation. Only patients presenting with no other SLE disease activity were included.Results.Isolated hematuria and/or pyuria were identified in 49 patients, of whom 17 were excluded according to the criteria above, leaving 32. Twenty-four patients had another renal manifestation 1 year before and/or after the occurrence; 27 had a non-renal manifestation 1 year before and/or after the occurrence; 3 patients had a biopsy in the same time frame, all with evidence of active lupus nephritis. Therefore the majority of patients with an occurrence of isolated hematuria and/or pyuria had evidence of renal or other non-renal SLE disease activity at a time adjacent to this presentation.Conclusion.Although not proven, our results suggest that these manifestations were associated with SLE activity, either before or after the episode, and therefore may represent a phase of active disease.

Background: Cysteine protease Cathepsin L is involved in bone remodeling and expressed in activated macrophages. It is highly expressed in metastatic tumor tissue, especially with bone metastases. Aims: We evaluated immunohistochemical expression of Cathepsin L in tumor cells and tumor-associated macrophages (TAMs) in chemo-naive Ewing sarcoma. Settings and Design: Retrospective evaluation of archived specimens of Ewing sarcoma. Materials and Methods: Immunohistochemical staining was performed on archived blocks of chemo-naive patients with Ewing sarcoma treated with uniform chemotherapy at our institute between January 2009 and November 2011. Statistical Analysis: Immunohistochemical expression was co-related with baseline demographics and survival. Results: During the study period, we had evaluable baseline samples from 62 patients with median age 15 years (range: 2-40); 26 (42%) had metastases. Cathepsin L expression in tumor cells was observed in 8/62 (13%) specimens. None of the baseline clinical characteristics correlated with Cathepsin L expression. Cathepsin L positivity was associated with poor response to neoadjuvant chemotherapy (NACT) (P = 0.05), but did not influence either event-free-survival (EFS) or overall survival. Cathepsin L was expressed in TAMs in all specimens. Grade 3 TAMs (>10 TAMs/high power field) was associated with better response to NACT (P = 0.05). On univariate analysis Grade 3 TAMs predicted superior EFS (median EFS 28.5 months in those with Grade 3 TAMs versus 14.8 months in those with grade ½ TAMs [P = 0.04]). Conclusions: Cathepsin L expression by immunohistochemistry was low in our patient cohort, and it did not affect the outcome. In addition, Grade 3 TAMs with Cathepsin L expression was associated with improved EFS.

The research objective was to identify and quantify the immunohistochemically (IHC) stained hepatic stellate cells (HSCs) in children with chronic hepatitis B (CHB), including staging (S), location in the hepatic lobule, and correlation with hepatocyte count. Retrospective morphological analysis was based on liver biopsies obtained from 70 CHB children before antiviral treatment. To determine fibrosis stage, the Batts and Ludwig scoring system was applied. Immunohistochemical examinations used monoclonal antibodies against - SMA. IHC observations in CHB children revealed a significant positive correlation between the mean number of SMA immunopositive HSCs within the hepatic lobule (r = 0.518; p < 0.001) and fibrosis stage. In biopsy specimens with intensive fibrosis, most HSCs had an elongated shape and demonstrated evidently strong immunoexpression of cytoskeletal protein - SMA. The mean counts of HSCs/100 hepatocytes (in high power field) in 4 study groups, i.e. with S-0, S-1, S-2, S-3, were 5.00; 5.98; 9.80; 12.19, respectively. Interestingly, in most groups the highest count of immunoreactive HSCs/100 hepatocytes was in the intermediate zone, indicating its high metabolic activity in liver fibrogenesis. Immunohistochemical and statistical investigations of HSCs in children with CHB showed a close positive correlation of cell count with fibrosis intensity, which may have prognostic implications in this pathology.

Pleomorphic xanthoastrocytoma (PXA) is usually a low grade astrocytic tumor. However, some cases show significant mitotic activity (5 or more mitosis per 10 High Power Field) and/or necrosis. These tumors are described as pleomorphic xanthoastrocytomas with anaplastic features and display increased risk of recurrence. We aimed to evaluate histopathological, immunohistochemical and molecular features of PXAs with anaplastic features, by reporting three primary cases displaying recurrence. Histopathologically we observed rhabdoid-like monomorphic atypical tumoral cells with increased mitotic activity, vascular endothelial proliferation and necrosis. Immunohistochemically, astrocytic and neuronal components displayed different specific staining properties. In 2 cases p53 was immunopositive. We detected BRAF V600E mutation in 2 cases and p16 mutation in one case, by fluorescence in situ hybridization (FISH) method. Anaplastic pleomorphic xanthoastrocytoma (APXA) is a rare tumor. We have presented 3 primary APXA cases displaying all characteristic histopathological features. Two of these cases were immunopositive for p53. Therefore, we think that this marker may not be so useful in differentiating APXA from glioblastoma (GBM). Two of our three cases display BRAF V600E mutation, which is compatible with the literature.

Objective To identify clinical and pathological differences between IgG4-related retroperitoneal fibrosis (IgG4-RPF) and idiopathic RPF (iRPF) in a Chinese population. Method Clinical and pathological data of 50 RPF patients from 2006 to 2016 were retrospectively analysed. The presence of at least one characteristic histopathological feature, >30 IgG4+ plasma cells per high power field, and an IgG4+/IgG+ plasma cells ratio cutoff of >40% were used to define IgG4-RPF. Results Patients with IgG4-RPF were significantly more likely to have pain (94.1 vs 68.8%, P = 0.048), elevated serum IgE concentration (166.1 vs 40.2 IU/ml, P = 0.029) and tissue eosinophilia (47.1 vs 12.5%, P = 0.018), compared with patients with iRPF. In the IgG4-RPF subgroup, patients with tissue eosinophilia demonstrated higher levels of CRP (4.3 vs 1.9 mg/dl, P = 0.027) and ESR (62.1 vs 22.8 mm/h, P = 0.001). Among the 50 patients with RPF, the average number of tissue IgG4+ plasma cells was positively correlated with the number of tissue eosinophils (r = 0.37, P = 0.009). Moreover, serum IgG4 concentration and serum IgE concentration showed positive correlation (r = 0.834, P = 0.000). Conclusion The distinct serological and histopathological features of Chinese patients with IgG4-RPF were elevated serum IgE concentration and tissue eosinophilia, which potentially can aid and support the diagnosis. As serum IgG4 concentration may be normal in patients with IgG4-RPF, serum IgE may represent a useful serological marker in distinguishing IgG4-RPF from iRPF.

Background Microscopic evaluation of urine is inconsistently performed in veterinary clinics. The IDEXX SediVue Dx® Urine Sediment Analyzer (SediVue) recently was introduced for automated analysis of canine and feline urine and may facilitate performance of urinalyses in practice. Objective Compare the performance of the SediVue with manual microscopy for detecting clinically relevant numbers of cells and 2 crystal types. Samples Five-hundred thirty urine samples (82% canine, 18% feline). Methods For SediVue analysis (software versions [SW] 1.0.0.0 and 1.0.1.3), uncentrifuged urine was pipetted into a cartridge. Images were captured and processed using a convolutional neural network algorithm. For manual microscopy, urine was centrifuged to obtain sediment. To determine sensitivity and specificity of the SediVue compared with manual microscopy, thresholds were set at ≥5/high power field (hpf) for red blood cells (RBC) and white blood cells (WBC) and ≥1/hpf for squamous epithelial cells (sqEPI), non-squamous epithelial cells (nsEPI), struvite crystals (STR), and calcium oxalate dihydrate crystals (CaOx Di). Results The sensitivity of the SediVue (SW1.0.1.3) was 85%-90% for the detection of RBC, WBC, and STR; 75% for CaOx Di; 71% for nsEPI; and 33% for sqEPI. Specificity was 99% for sqEPI and CaOx Di; 87%-90% for RBC, WBC, and nsEPI; and 84% for STR. Compared to SW1.0.0.0, SW1.0.1.3 had increased sensitivity but decreased specificity. Performance was similar for canine versus feline and fresh versus stored urine samples. Conclusions and clinical importance The SediVue exhibits good agreement with manual microscopy for the detection of most formed elements evaluated, but improvement is needed for epithelial cells.

Here we report a retrospective cross-sectional study on Esophageal eosinophilia (EsEo) frequency in Brazil, for 2, 425 pediatric patients with symptoms associated with gastroesophageal diseases in 2012. EsEo is defined by ≥15 eosinophils per high power field (400x) and confirmed through histological analyses of esophageal biopsies. Overall, 126 patients had EsEo equating to a frequency of 5.2%. There was a significant difference between the endoscopic features of patients with EsEo, where 10.7% had erosive esophagitis, 3.0% had non-erosive esophagitis and 1% showed normal esophageal mucosa. According to the interaction of the variables in the Classification and Regression Tree Analysis, most patients diagnosed with EsEo were older males with erosive esophagitis. On the other hand, the lowest frequency of EsEo was found among younger females with non-erosive esophagitis/normal mucosa. Environmental conditions, including climate variation and changes, were observed in association with EsEo, supporting a potential role for environmental factors in its pathogenesis. There was an inverse correlation between the number of EsEo, rainfall and humidity. EsEo is a relatively frequent finding in the pediatric population of Brazil with symptoms of gastroesophageal diseases. Both clinical and histological examinations of patients are important for a reliable diagnostic of EsEo cases and to patient care.

Background Anal high-grade squamous intraepithelial lesions (HSILs) are the precursors to anal cancer and frequently persist or recur following electrocautery ablation (EA). Impaired mucosal immunity may facilitate anal carcinogenesis. We characterized the immune microenvironment of anal HSILs in correlation with human immunodeficiency virus (HIV) serostatus and ablation outcomes. Methods Using immunohistochemistry, mucosa-infiltrating CD4+ and CD8+ lymphocytes were quantified in HSILs and benign mucosa from 70 HIV+ and 45 HIV- patients. Clinicopathological parameters were compared. Results Anal HSILs harbored more T lymphocytes than benign mucosa regardless of HIV status (P ≤ .03). Total T lymphocyte count and CD8+ subset were significantly higher in HIV+ HSILs versus HIV- HSILs (median cell count, 71 vs 47; 47 vs 22/high power field [HPF]; P < .001), whereas the CD4+ subset was comparable between groups (median, 24 vs. 25; P = .40). Post EA, HSILs persisted in 41% of HIV+ and 19% of HIV- patients (P = .04). Unadjusted analysis showed trends toward EA failures associated with HIV seropositivity (incidence rate ratio [IRR], 2.0; 95% CI, .8-4.9) and increased CD8+ cells (IRR, 2.3; 95% CI, .9-5.3). Conclusions Human immunodeficiency virus is associated with alterations of the immune microenvironment of anal HSILs manifested by increased local lymphocytic infiltrates, predominately CD8+. Human immunodeficiency virus seropositivity and excess mucosa-infiltrating CD8+ cells may be associated with ablation resistance.

The study analyzed the influence of synovitis on the histological and biomechanical properties of lateral-compartment cartilage. In a prospective cohort study, 84 patients (100 knees) with varus deformity of the knee were included. Osteochondral samples from the distal lateral femur underwent biomechanical and histologic analysis. Synovial tissue was sampled for histological (chronic synovitis score) and immunohistochemical evaluation of the degree of synovitis. CD15 (neutrophils), Ki-67 (dividing cells), and CD68 (macrophages) were tested in all synovial samples. While the histological synovitis score did not correlate with the degree of cartilage degeneration (histological OARSI grades), both CD15 (rs = 0.297, p = 0.006) and Ki-67 (rs = 0.249, p = 0.023) correlated with histological OARSI grades. There was a weak negative correlation of CD15 with biomechanical properties of cartilage of the distal lateral femur (aggregate modulus (Ha): rs = −0.125; p = 0.257; dynamic modulus (DM): rs = −0.216; p = 0.048). No correlations were observed for Ki-67 and CD68. In addition, biomechanical properties were inferior in knees with a CD15 of >8/high power field compared to knees with a CD15 of ≤8/high power field (Ha: p = 0.031, d = 0.46; DM: p = 0.005, d = 0.68). The study demonstrates an association of increased inflammatory activity with advanced cartilage degeneration. Lateral-compartment cartilage in knees with elevated synovial CD15 counts has a reduced ability to withstand compressive loads. CD15 might serve as an indicator for inferior biomechanical cartilage properties. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Background Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized systemic inflammatory disease with multi-organ involvement [1]. Diagnostically, two of the most important hallmarks of IgG4-RD are high IgG4-positive plasma cell (PC) counts and high IgG4/IgG ratios in affected organs. Although the International consensus statement (ICS) on the pathology of IgG4-RD adopted different IgG4-positive PC counts among affected organs for the diagnosis to differentiate IgG4-RD mimickers from IgG4-RD [2], histological and immunohistochemical findings of the specimens from not only one but multiple organs in the same patient has not been evaluated. Objectives This study aimed to investigate the diagnostic sensitivity of the cutoff values of IgG4-positive PC number and IgG4-positive/CD138-positive cell ratio proposed by the International consensus statement (ICS) on the pathology of IgG4-RD in typical multiple lesions of patients with IgG4-RD. Methods We evaluated IgG4-positive PC number and IgG4-positive/CD138-positive cell ratio in 35 samples from 16 IgG4-RD patients having more than two typical lesions of IgG4-RD. Results We evaluated twelve submandibular, eleven ophthalmic, four skin, four kidney, two pancreatic, and one bronchus and prostate lesion each in 16 patients with typical clinical, serological, and radiographic features. Concerning IgG4+ PC number per high power field, most ophthalmic (8/11), kidney (4/4), pancreatic (2/2), and bronchial lesions (1/1) fulfilled the cutoff value of ICS, whereas many of the submandibular (5/12) and skin lesions (0/4) did not. In contrast to the absolute number, almost all lesions fulfilled the cutoff value of IgG4+/CD138+ cell ratio. In five cases, only one or two lesions in the same patient fulfilled the cutoff value of ICS, while the others did not. Conclusions These results suggest that ICS criteria have different sensitivities among the affected organs in diagnosing IgG4-RD. References Stone JH, et al. IgG4-related disease. N Engl J Med. 2012;366:539–51. Deshpande V, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25:1181–92. Disclosure of Interest None declared

Background IgG4 related disease (IgG4RD) is a spectrum of immune mediated disease with multiple organs involvement characterized by organ enlargement, function loss or obstructive symptoms (1, 2). Objectives In this retrospective study, clinical, serological and histological features of IgG4RD patients over the past ten years from four regional hopsitals were reviewed. Methods Four regional hospitals participated with study period from 1/1/2006 to 30/6/2016. IgG4RD patients were classifed into definite, probable and possible IgG4RD according to Japanese Comprehensive Diagnostic Criteria for IgG4RD (3). Statistical analysis: Association between the individual categorical covariates and the different organ involvement were analyzed by Fisher9s exact test. Results 108 patients were included. There were 81 male patients and 27 female patients and the male to female ratio is 3:1. The mean age of diagnosis was 62.8 year old. 57 patients were diagnosed as definite IgG4RD (53%), 14 patients as probable IgG4RD (13%) and 37 patients as possible IgG4RD (34%). Salivary glands involvement was the commonest, (M=45.7% vs F=33.3%), followed by pancreas (M=28.4% vs F=18.5%) and biliary system in male (M=24.7% vs F=11.1%) and orbital in female (M=23.5% vs F=18.5%). 53% patients also had multi organ involvement. 104 patients had serum IgG4 level checked and it was raised in 94 patients (90.4%). 77 patients (74.0%) had IgG4 level above twice upper limit of normal. IgG4 level was normal in 10 patients. 98% and 86.3% patients with multi organ involvement had IgG4 level >135mg/dL (p=0.016) and >270mg/dL (p=0.007) respectively. In the hepatobiliary group (n=36), 30 patients had blood checked for Ca19.9 level and it was raised in 17 patients (56.7%), with the highest level 14127 U/ml. 71 histological reports were available. Lymphoplasmacytic infiltration was a consistent features in all specimens (100%). Eosinophilic infiltration was seen in 19 specimen (27%). Fibrosis was seen in 44 specimens (63%). Sialadenitis and dacryoadenitis were associated with dense fibrosis. Obliterative phlebitis was seen in 7 specimens (10%). IgG4/IgG ratio was reported in 61 specimens. 53 specimens had IgG4/IgG ratio greater than 40% per high power field which accounted for 86.9% of the specimens. Conclusions Most patients were male with the peak diagnosis at age 50 to 70. Salivary gland and pancreas were the most common organ involved. Most patients had a raised IgG4 level and most histological specimens showed a raised IgG4/IgG ratio on immunostaining. IgG4 level twice the upper limit of normal was quite specific for the disease and was associated with multi organ involvement. References Pieringer H, et al. IgG4- related disease: an orphan disease with many faces. Orphanet journal of rare diseases. 2014;9:110. Haitao Du YW et al. IgG4-related disease and the curreny status of diagnostic approaches. EXCLI. 2012;11:651–8. Umehara H, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Modern Rheumatology. 2012;22(1):21–30. Disclosure of Interest None declared

Background: Breast cancer is the leading cause of cancer - related deaths in Asia. The number of intra-nuclear silver stained structures, termed AgNORs, is significantly higher in malignant cells than in normal, reactive or benign cells. The purpose of this study was to evaluate the AgNOR scores in FNA smears of breast lesions and their correlation with histopathology. Aims & Objective: To establish AgNOR staining as a diagnostic and prognostic tool in management of various breast lesions. Methods: This was a prospective study conducted over a period of 18 months may 2015 to November 2016. A total of 100 cases were included in the study. AgNOR stain was done in both cytology and scoring was done and analysed. Results: In FNAC aspirates, Mean AgNOR count ranged from 5 to 9.9 per high power field with a mean value of 2.888±2.553. The AgNOR dots morphology was homogenous, symmetric with regular contours in FNAC slides of benign breast lesion. In malignant breast lesions, the dots were asymmetric with irregular contours and were aggregated, smaller and more scattered. Conclusions: The present study showed that fine needle aspiration cytology is a useful modality for diagnosis of breast lesions. It has a high concordance with the histopathology . AgNOR count assessment provides a useful objective measure for segregation of different grades of tumor with 100% accuracy for detection of higher grade of lesions, as observed in present study. For differentiation of benign from malignant lesions too it has a high sensitivity as well as specificity. The usefulness of FNAC to evaluate nodal involvement also showed a 90% sensitivity and 95.6% specificity. On the basis of present study, it could be concluded that AgNOR count estimation using fine needle aspiration is a useful method to differentiate and diagnose breast lesions.

Eosinophilic Esophagitis (EoE) is an inflammatory disease caused by inhaled or ingested food allergies, and characterized by the infiltration of eosinophils in the esophagus. The gold standard for diagnosing EoE is to conduct endoscopy and obtain multiple biopsy specimens from different portions of the esophagus; an exam is considered positive if more than 15 eosinophils per high power field (HPF) in any of the biopsies. This method of diagnosis is problematic because endoscopic biopsy is expensive and poorly tolerated and the esophageal eosinophil burden needs to be monitored frequently during the course of the disease. Spectrally encoded confocal microscopy (SECM) is a high-speed confocal microscopy technology that can visualize individual eosinophils in large microscopic images of the human esophagus, equivalent to more than 30,000 HPF. Previously, we have demonstrated that tethered capsule SECM can be conducted in unsedated subjects with diagnosed EoE. However, speckle noise and the relatively low resolution in images obtained with the first capsule prototypes made it challenging to distinguish eosinophils from other cells. In this work, we present a next-generation tethered SECM capsule, which has been modified to significantly improve image quality. First, we substituted the single mode fiber with a dual-clad fiber to reduce speckle noise. A gradient-index multimode fiber was fusion spliced at the tip of the dual-clad fiber to increase the effective numerical aperture of the fiber from 0.09 to 0.15, expanding the beam more rapidly to increase the illumination aperture at the objective. These modifications enabled the new SECM capsule to achieve a lateral resolution of 1.8 µm and an axial resolution of 16.1 µm, which substantially improves the capacity of this probe to visualize cellular features in human tissue. The total size of the SECM capsule remained 6.75 mm in diameter and 31 mm in length. We are now in the process of testing this new SECM capsule in humans. Early results using this new SECM capsule suggest that this technology has the potential to be an effective tool for the diagnosis of EoE.

Background Eosinophilic oesophagitis (EoE) is a chronic disease, driven by food allergens. Elemental diets are effective for the management of children with EoE, but studies on the effect of elemental diets in adults are scarce and poor palatability challenges dietary adherence. Aim To assess the effects of an elemental diet (Neocate, Nutricia, Utrecht, the Netherlands) on the inflammation, symptoms and endoscopic signs in adultEoE patients. Methods In this prospective study, 21 patients with active EoE, confirmed by biopsies showing >= 15 eosinophils per microscopic high power field (HPF) and symptoms of oesophageal dysfunction were included. Patients underwent endoscopy before and 4 weeks after diet. Histological disease activity (peak eosinophil count/HPF), and endoscopic signs were scored by physicians. Symptoms and adherence to the diet were evaluated by questionnaires. Serum total IgE levels and total eosinophil counts were determined and the expression of inflammatory cytokines was analysed by qPCR. Results In total, 17 (81%) of the patients completed the diet, of whom 12 (71%) showed complete histological response ( = 50% reduction of baseline eosinophil count). Peak eosinophil counts decreased significantly after the diet from 40 to 9 per HPF (P