Immunohistochemical detection of double-stranded RNA in formalin-fixed paraffin-embedded tissue.

Double-stranded RNA (dsRNA) is produced during most viral infections, and immunohistochemical detection of dsRNA has been proposed as a potential screening marker for viral replication. The anti-dsRNA monoclonal antibody clone 9D5 is more sensitive than the established clone J2 but has not been validated in formalin-fixed paraffin-embedded (FFPE) tissue. This study aimed to test and compare the performance of the anti-dsRNA monoclonal antibodies, 9D5 and J2, in FFPE tissue using an automated staining platform. Archived clinical tissue samples with viral infections (n = 34) and uninfected controls (n = 30) were examined. Immunohistochemical staining for dsRNA (9D5 and J2) and virus-specific epitopes was performed. 9D5 provided a similar staining pattern but a higher signal-to-noise ratio than J2. The following proportions of virus-infected tissue samples were dsRNA-positive: SARS-CoV-2 (5/5), HPV (6/6), MCV (5/5), CMV (5/6), HSV (4/6), and EBV (0/6). Also, 18 of 30 uninfected samples were dsRNA positive, and an association between fixation time and intensity was observed. However, signals in all samples were markedly reduced by pretreatment with dsRNA-specific RNAse-III, indicating a specific reaction. In conclusion, dsRNA can be demonstrated in most viral infections with immunohistochemistry in FFPE tissue but with low clinical specificity. The antibody clone 9D5 performs better than clone J2.

Lessons Learned, Challenges Taken, and Actions Made for "Precision" Immunohistochemistry. Analysis and Perspectives From the NordiQC Proficiency Testing Program.

Immunohistochemistry (IHC) has for decades been an integrated method within pathology applied to gain diagnostic, prognostic, and predictive information. However, the multimodality of the analytical phase of IHC is a challenge to ensure the reproducibility of IHC, which has been documented by external quality assessment (EQA) programs for many biomarkers. More than 600 laboratories participate in the Nordic immunohistochemical Quality Control EQA program for IHC. In the period, 2017-2021, 65 different biomarkers were assessed and a total of 31,967 results were evaluated. An overall pass rate of 79% was obtained being an improvement compared with 71% for the period, 2003-2015. The pass rates for established predictive biomarkers (estrogen receptor, progesterone receptor, and HER2) for breast carcinoma were most successful showing mean pass rates of 89% to 92%. Diagnostic IHC biomarkers as PAX8, SOX10, and different cytokeratins showed a wide spectrum of pass rates ranging from 37% to 95%, mean level of 75%, and attributed to central parameters as access to sensitive and specific antibodies but also related to purpose of the IHC test and validation performed accordingly to this. Seven new diagnostic biomarkers were introduced, and all showed inferior pass rates compared with the average level for diagnostic biomarkers emphasizing the challenge to optimize, validate, and implement new IHC biomarkers. Nordic immunohistochemical Quality Control operates by "Fit-For-Purpose" EQA principles and for programmed death-ligand 1, 2 segments are offered aligned to the "3-dimensional" approach-bridging diagnostic tests, drugs to be offered, and diseases addressed. Mean pass rates of 65% and 79% was obtained in the 2 segments for programmed death-ligand 1.

Comparison of Antibodies to Detect Uroplakin in Urothelial Carcinomas.

Immunohistochemistry for Uroplakin (UP) II and III is used to determine urothelial origin of carcinomas of unknown primary site and are especially valuable to differentiate urothelial carcinomas (UCs) from lung squamous cell carcinomas and prostate carcinomas. In the Nordic immunohistochemical Quality Control assessment scheme, only 45% of the participants obtained a sufficient staining result for UP. Primary antibodies (Abs) against UPII were most successful with a pass rate of 86%. No Abs against UPIII provided sufficient staining results. A comparative study was carried out on a larger cohort of tissue samples with optimized methods for the UPII mouse monoclonal antibody (mmAb) clone BC21, UPIII mmAb clone AU-1, and rabbit monoclonal antibody (rmAb) clone SP73 to evaluate the performance in a standardized way. Tissue microarrays containing 58 UCs, 111 non-UCs, and 20 normal tissues were included. The UP stains were evaluated by using H-score. Based on H-scores, samples were categorized as high-expressor (150 to 300), moderate-expressor (10 to 149), low-expressor (1 to 9), and negative (<1). The UPII mmAb clone BC21 obtained a significant higher analytical sensitivity of 69% for UCs compared with the UPIII Abs mmAb clone AU-1 and rmAb clone SP73 with 19% and 29%, respectively. No high-expressor UCs were seen for the UPIII Abs, whereas 13% of the positive UCs obtained an H-score >150 for the UPII Ab. The 2 UPIII Abs gave an analytical specificity of 100% compared with 97% for the UPII Ab being positive in 2 ovarian carcinomas and 1 cervical squamous cell carcinoma.

Variability in Breast Cancer Biomarker Assessment and the Effect on Oncological Treatment Decisions: A Nationwide 5-Year Population-Based Study.

We compared estrogen receptor (ER), progesterone receptor (PR), human epidermal growth-factor receptor 2 (HER2), Ki67, and grade scores among the pathology departments in Sweden. We investigated how ER and HER2 positivity rates affect the distribution of endocrine and HER2-targeted treatments among oncology departments. All breast cancer patients diagnosed between 2013 and 2018 in Sweden were identified in the National Quality Register for Breast Cancer. Cases with data on ER, PR, HER2, Ki67, grade, and treatment were selected (43,261 cases from 29 departments following the guidelines for biomarker testing). The ER positivity rates ranged from 84.2% to 97.6% with 6/29 labs out of the overall confidence intervals (CIs), while PR rates varied between 64.8% and 86.6% with 7/29 labs out of the CIs. HER2 positivity rates ranged from 9.4% to 16.3%, with 3/29 labs out of the overall CIs. Median Ki67 varied between 15% and 30%, where 19/29 labs showed significant intra-laboratory variability. The proportion of grade-II cases varied between 42.9% and 57.1%, and 13/29 labs were outside of the CI. Adjusting for patient characteristics, the proportion of endocrine and anti-HER2 treatments followed the rate of ER and HER2 positivity, illustrating the clinical effect of inter- and intra-laboratory variability. There was limited variability among departments in ER, PR, and HER2 testing. However, even a few outlier pathology labs affected endocrine and HER2-targeted treatment rates in a clinically relevant proportion, suggesting the need for improvement. High variability was found in grading and Ki67 assessment, illustrating the need for the adoption of new technologies in practice.

Ki-67 Proliferation Index in Breast Cancer as a Function of Assessment Method: A NordiQC Experience.

Immunohistochemical staining for Ki-67 is used to calculate a Ki-67 proliferation index (PI) that carries prognostic and predictive information in various cancers including breast carcinomas. Studies have documented challenges for observers to reproducibly estimate the Ki-67 PI. At present, no international consensus exists concerning scoring method (eg, hotspots vs. overall average, digital vs. manual counting) or even the definition of a Ki-67-positive cell. To clarify the approach to Ki-67 scoring and evaluation of the interobserver agreement among participants in the Nordic Immunohistochemical Quality Control (NordiQC) Breast Cancer Module, a study was set up on the basis of an online web module containing 15 digitized tissue microarray cores of breast carcinomas stained for Ki-67 in the NordiQC reference laboratory. All participants were invited to attend the study. In addition to Ki-67 scoring, they were asked to disclose their preferred method for Ki-67 estimation and their job title. For comparison, slides were analyzed using a Digital Image Analysis algorithm based on Virtual Double Staining. In total, 199 participants enrolled for the study. Overall, there was a good correlation in Ki-67 PIs among the participants, although results for some cores varied significantly. However, when applying a cutoff of 20%, a relatively low κ value of 0.52 was observed. Participants scoring in hotspots reported higher Ki-67 PIs than participants estimating an overall average, and, not surprisingly, participants who considered weak Ki-67 nuclear staining positive obtained higher Ki-67 PIs than those who did not. Ki-67 PI was not correlated to job title. The Virtual Double Staining algorithm obtained Ki-67 values close to the mean value of the human observers. Our study underlines the need for international standardization and guidelines in estimation of Ki-67 PI. Digital Image Analysis may be a useful tool in this process.

NordiQC Assessments of Keratin 5 Immunoassays.

This paper is number 7 in a series developed through a partnership between ISIMM and NordiQC with the purpose of reporting research assessing the performance characteristics of immunoassays in an external proficiency testing program.

Automatic Bone Marrow Cellularity Estimation in H&E Stained Whole Slide Images.

Bone marrow cellularity is an important measure in diagnostic hematopathology. Currently, the gold standard for bone marrow cellularity estimation is manual inspection of hematoxylin and eosin stained whole slide images (H&E WSI) by hematopathologists. However, these assessments are subjective and subject to interobserver and intraobserver variability. This may be reduced by using a computer-assisted estimate of bone marrow cellularity. The aim of this study was to develop a fully automated algorithm to estimate bone marrow cellularity in H&E WSI stains using bone marrow segmentation. Data consisted of eight bone marrow H&E WSIs extracted from eight subjects. An algorithm was developed to estimate the bone marrow cellularity consisting of biopsy segmentation, tissue classification, and bone marrow segmentation. Segmentations of the red and yellow bone marrow (YBM) were used to estimate the bone marrow cellularity within the WSI H&E stains. The DICE coefficient between automatic tissue segmentations and ground truth segmentations conducted by an experienced hematopathologist were used for validation. Furthermore, the agreement between the automatic and two manual cellularity estimates was assessed using Bland-Altman plots and intraclass correlation coefficients (ICC). The validation of the bone marrow segmentation demonstrated an average DICE of 0.901 and 0.920 for the red and YBM, respectively. A mean cellularity estimate difference of -0.552 and - 7.816 was obtained between the automatic cellularity estimates and two manual cellularity estimates, respectively. An ICC of 0.980 (95%CI: 0.925-0.995, P-value: 5.51 × 10-7 ) was obtained between the automatic and manual cellularity estimates based on manual annotations. The study demonstrated that it was possible to obtain bone marrow cellularity estimates with a good agreement with bone marrow cellularity estimates obtained from an experienced hematopathologist. © 2019 International Society for Advancement of Cytometry.

Impact of Primary Antibody Clone, Format, and Stainer Platform on Ki67 Proliferation Indices in Breast Carcinomas.

Ki67 is a nuclear protein expressed during the active phases of the cell cycle, which makes it a biomarker of cell proliferation. In clinical pathology settings, immunohistochemical (IHC) detection of Ki67 is used to calculate Ki67 proliferation indices (PIs), which have prognostic information and are used to subdivide breast carcinomas and neuroendocrine neoplasias. Calculation of Ki67 PIs is notoriously hard and prone to intraobserver and interobserver variance. In addition, IHC protocol settings [such as primary antibody (Ab) clone, clone format, and stainer platform] can affect the result of the IHC assays and in turn the Ki67 PI. Digital image analysis has been suggested as a useful tool to standardize Ki67 counting. Recently, virtual double staining, a computer algorithm segmenting Ki67 and Ki67 tumor cells using digitally fused parallel cytokeratin and Ki67-stained slides, has been introduced. In this study, we compare Ki67 PIs obtained by virtual double staining in 41 breast carcinomas stained using the most commonly used commercially available primary Ab clones and formats on the main stainer platforms. IHC protocols for the concentrated (conc) Ab and platform combinations were optimized for the highest analytical sensitivity and optimal signal-to-noise ratio, whereas ready-to-use (RTU) formats were used, as recommended by the vendor. Significant differences in the mean Ki67 PIs (relativized to the mean core Ki67) were observed not only between the different Ab clones but also the different formats and stainer platforms; Ki67 PIs with SP6 conc stained on the Ventana BenchMark ULTRA platform were on average 11.9 percentage points (pp) higher than the mean core average, whereas with Ab 30.9 RTU on the Ventana platform, they were 10.4 pp higher. Mib1 RTU (Dako Autostainer Link 48) and MM1 RTU (Leica Bond) provided 8.6 and 12.5 pp lower Ki67 PIs, respectively. Mib1 conc and SP6 conc on the Dako Autostainer and Leica Bond provided similar results-close to the overall average. Significant variations in the proportion of tumors with Ki67 high-level expression (Ki67 PI ≥20%) were observed among Ab, format, and stainer platform combinations. The results underline the challenges in the comparison of Ki67 PIs across Abs, formats, and platforms. Researchers and clinicians need to account for these differences when reporting Ki67 PIs. To advance the usefulness of Ki67 PIs in the research and clinical setting, standardization of Ki67 IHC assays is needed.

Primary Mediastinal Choriocarcinoma in an Elderly Patient with Concurrent Goserelin-Treated Prostate Adenocarcinoma.

Mediastinal pure choriocarcinomas are exceedingly rare representations of germ cell tumours and are associated with a poor prognosis. To date, fewer than 20 cases have been reported. This current report describes an elderly patient who developed a large rapidly growing mediastinal tumour. Unfortunately, the patient expired before a definitive diagnosis could be reached. An autopsy revealed that the histomorphological features of the tumour showed two distinct tumour cell populations (syncytio- and cytotrophoblasts), and the diagnosis of choriocarcinoma was made. Immunohistochemical analysis showed a characteristic staining pattern in agreement with published studies. Here, we report a case of primary mediastinal choriocarcinoma in an elderly male with concurrent metastasizing prostate adenocarcinoma treated with long-term goserelin deposits, which, as we speculate, could have induced the choriocarcinoma.

High CXCR4 expression impairs rituximab response and the prognosis of R-CHOP-treated diffuse large B-cell lymphoma patients.

Survival of diffuse large B-cell lymphoma (DLBCL) patients has improved by inclusion of rituximab. Refractory/recurrent disease caused by treatment resistance is, however, a major problem. Determinants of rituximab sensitivity are not fully understood, but effect of rituximab are enhanced by antagonizing cell surface receptor CXCR4. In a two-step strategy, we tested the hypothesis that prognostic value of CXCR4 in DLBCL relates to rituximab treatment, due to a hampering effect of CXCR4 on the response of DLBCL cells to rituximab. First, by investigating the prognostic impact of CXCR4 mRNA expression separately for CHOP (n=181) and R-CHOP (n=233) cohorts and, second, by assessing the interaction between CXCR4 and rituximab in DLBCL cell lines. High CXCR4 expression level was significantly associated with poor outcome only for R-CHOP-treated patients, independent of IPI score, CD20 expression, ABC/GCB and B-cell-associated gene signature (BAGS) classifications. s. For responsive cell lines, inverse correlation was observed between rituximab sensitivity and CXCR4 surface expression, rituximab induced upregulation of surface-expressed CXCR4, and growth-inhibitory effect of rituximab increased by plerixafor, supporting negative impact of CXCR4 on rituximab function. In conclusion, CXCR4 is a promising independent prognostic marker for R-CHOP-treated DLBCL patients, possibly due to inverse correlation between CXCR4 expression and rituximab sensitivity.

Quality assessment of Ki67 staining using cell line proliferation index and stain intensity features.

Breast cancer is the most frequent cancer among women worldwide. Ki67 can be used as an immunohistochemical pseudo marker for cell proliferation to determine how aggressive the cancer is and thereby the treatment of the patient. No standard Ki67 staining protocol exists, resulting in inter-laboratory stain variability. Therefore, it is important to determine the quality control of a staining protocol to ensure correct diagnosis and treatment of patients. Currently, quality control is performed by the organization NordiQC that use an expert panel-based qualitative assessment system. However, no objective method exists to determine the quality of a staining protocol. In this study, we propose an algorithm, to objectively assess staining quality from segmented cell nuclei structures extracted from cell lines. The cell nuclei were classified into either Ki67 positive or negative to determine the Ki67 proliferation index within the cell lines. A Ki67 stain quality model based on ordinal logistic regression was developed to determine the quality of a staining protocol from features extracted from the segmented cell nuclei in the cell lines. The algorithm was able to segment and classify Ki67 positive cell nuclei with a sensitivity and positive predictive value (PPV) of 0.90 and 0.94 and Ki67 negative cell nuclei with a sensitivity and PPV of 0.78 and 0.78. The mean difference between a manual and automatic Ki67 proliferation index was -0.003 with a standard deviation of 0.056. The ordinal logistic regression model found that the stain intensity for both the Ki67 positive and Ki67 negative cell nuclei were statistically significant as parameters determining the stain quality from the cell line cores. The framework shows great promise for using cell nuclei information from cell lines to predict the staining quality of staining protocols. © 2018 International Society for Advancement of Cytometry.

NordiQC Assessments of CD117 Immunoassays.

This paper is the number 5 in a series developed through a partnership between ISIMM and NordiQC for the purpose of reporting research assessing the performance characteristics of immunoassays in an external proficiency-testing program.

Using cell nuclei features to detect colon cancer tissue in hematoxylin and eosin stained slides.

Currently, diagnosis of colon cancer is based on manual examination of histopathological images by a pathologist. This can be time consuming and interpretation of the images is subject to inter- and intra-observer variability. This may be improved by introducing a computer-aided diagnosis (CAD) system for automatic detection of cancer tissue within whole slide hematoxylin and eosin (H&E) stains. Cancer disrupts the normal control mechanisms of cell proliferation and differentiation, affecting the structure and appearance of the cells. Therefore, extracting features from segmented cell nuclei structures may provide useful information to detect cancer tissue. A framework for automatic classification of regions of interest (ROI) containing either benign or cancerous colon tissue extracted from whole slide H&E stained images using cell nuclei features was proposed. A total of 1,596 ROI's were extracted from 87 whole slide H&E stains (44 benign and 43 cancer). A cell nuclei segmentation algorithm consisting of color deconvolution, k-means clustering, local adaptive thresholding, and cell separation was performed within the ROI's to extract cell nuclei features. From the segmented cell nuclei structures a total of 750 texture and intensity-based features were extracted for classification of the ROI's. The nine most discriminative cell nuclei features were used in a random forest classifier to determine if the ROI's contained benign or cancer tissue. The ROI classification obtained an area under the curve (AUC) of 0.96, sensitivity of 0.88, specificity of 0.92, and accuracy of 0.91 using an optimized threshold. The developed framework showed promising results in using cell nuclei features to classify ROIs into containing benign or cancer tissue in H&E stained tissue samples. © 2017 International Society for Advancement of Cytometry.

Accurate PD-L1 Protocols for Non-Small Cell Lung Cancer can be Developed for Automated Staining Platforms With Clone 22C3.

Treatment using immunotherapy against PD-L1 or PD-1 has become one of the hottest topics in Pathology and Oncology. Correct selection of patients eligible for treatment requires optimal immunohistochemical staining protocols. Treatment with pembrolizumab requires diagnostic examination of the patient's tumour using the companion diagnostic Ready-To-Use pharmDx kit from Dako Agilent based on the mAb 22C3 clone on the Autostainer platform. However, not all diagnostic pathology labs have access to this staining platform. This purpose of this study was to develop and validate protocols for PD-L1 detection for all major staining platforms using the concentrated format of 22C3 that would give similar staining result (equal Tumour Proportion Scores) to the pharmDx kit.

Quantitative tumor heterogeneity assessment on a nuclear population basis.

Immunohistochemistry Ki-67 stain is widely used for visualizing cell proliferation. The common method for scoring the proliferation is to manually select and score a hot spot. This method is time-consuming and will often not give reproducible results due to subjective selection of the hotspots and subjective scoring. An automatic hotspot detection and proliferative index scoring would be time-saving, make the determination of the Ki-67 score easier and minimize the uncertainty of the score by introducing a more objective and standardized score. Tissue Micro Array cores stained for Ki-67 and their neighbor slide stained for Pan Cytokeratin were aligned and Ki-67 positive and negative nuclei were identified inside tumor regions. A heatmap was calculated based on these and illustrates the distribution of the heterogenous response of Ki-67 positive nuclei in the tumor tissue. An automatic hot spot detection was developed and the Ki-67 score was calculated. All scores were compared with scores provided by a pathologist using linear regression models. No significant difference was found between the Ki-67 scores guided by the developed heatmap and the scores provided by a pathologist. For comparison, scores were also calculated at a random place outside the hot spot and these scores were found to be significantly different from the pathologist scores. A heatmap visualizing the heterogeneity in tumor tissue expressed by Ki-67 was developed and used for an automatic identification of hot spots in which a Ki-67 score was calculated. The Ki-67 scores did not differ significantly from scores provided by a pathologist. © 2017 International Society for Advancement of Cytometry.

Proliferation assessment in breast carcinomas using digital image analysis based on virtual Ki67/cytokeratin double staining.

Manual estimation of Ki67 Proliferation Index (PI) in breast carcinoma classification is labor intensive and prone to intra- and interobserver variation. Standard Digital Image Analysis (DIA) has limitations due to issues with tumor cell identification. Recently, a computer algorithm, DIA based on Virtual Double Staining (VDS), segmenting Ki67-positive and -negative tumor cells using digitally fused parallel cytokeratin (CK) and Ki67-stained slides has been introduced. In this study, we compare VDS with manual stereological counting of Ki67-positive and -negative cells and examine the impact of the physical distance of the parallel slides on the alignment of slides. TMAs, containing 140 cores of consecutively obtained breast carcinomas, were stained for CK and Ki67 using optimized staining protocols. By means of stereological principles, Ki67-positive and -negative cell profiles were counted in sampled areas and used for the estimation of PIs of the whole tissue core. The VDS principle was applied to both the same sampled areas and the whole tissue core. Additionally, five neighboring slides were stained for CK in order to examine the alignment algorithm. Correlation between manual counting and VDS in both sampled areas and whole core was almost perfect (correlation coefficients above 0.97). Bland-Altman plots did not reveal any skewness in any data ranges. There was a good agreement in alignment (>85 %) in neighboring slides, whereas agreement decreased in non-neighboring slides. VDS gave similar results compared with manual counting using stereological principles. Introduction of this method in clinical and research practice may improve accuracy and reproducibility of Ki67 PI.

Immunohistochemical expression of HER2 in breast cancer: socioeconomic impact of inaccurate tests.

BACKGROUND: Treatment for patients with breast cancer (BC) is guided by human epidermal growth factor receptor 2 (HER2) status. The patient's HER2 status is assessed using US Food and Drug Administration-approved in vitro diagnostic (IVD) immunohistochemical (IHC) tests and laboratory-developed IVD tests. We analysed HER2 testing accuracy using data from the Nordic Immunohistochemistry Quality Control (NordiQC) HER2 IHC programme; results were used in an economic BC treatment model. METHODS: Data were obtained from NordiQC HER2 BC surveys performed from 2008 to 2012. False-negative (FN) and false-positive (FP) rates for approved and laboratory-developed IVDs were used to estimate direct costs, loss of survival, productivity benefit and quality-adjusted life-years. In the absence of consistent and accessible clinical and economic data from countries participating in the NordiQC programme, United States productivity data, healthcare costs and patient numbers were used as a surrogate in order to estimate the potential impact of selecting an approved or laboratory-developed IVDs. RESULTS: In total, 1703 tests were performed. Pooled FN rates were 11% for approved IVDs and 25% for laboratory-developed IVDs; FP rates were 0% and 5%, respectively. Using these FP and FN rates in the economic model and applying them to the United States BC population, approved IVD tests would result in better clinical outcomes, i.e., better survival and fewer disease recurrences/progressions, and lower costs, i.e., total direct costs and lost productivity, versus laboratory-developed IVD tests. Every $1 saved by laboratories by using cheaper reagents could potentially result in approximately $6 additional costs to the healthcare system. CONCLUSIONS: The results of this analysis suggest that incorrect HER2 test results have far-reaching clinical and economic consequences.

Soluble urokinase-type plasminogen activator receptor levels in patients with schizophrenia.

BACKGROUND: The etiology of schizophrenia remains largely unknown but alterations in the immune system may be involved. In addition to the psychiatric symptoms, schizophrenia is also associated with up to 20 years reduction in life span. Soluble urokinase-type plasminogen activator receptor (suPAR) is a protein that can be measured in blood samples and reflects the levels of inflammatory activity. It has been associated with mortality and the development of type 2 diabetes and cardiovascular disease. METHODS: suPAR levels in patients with schizophrenia were compared to healthy controls from the Danish Blood Donor Study. SuPAR levels were dichotomized at >4.0 ng/ml, which is considered the threshold for low grade inflammation. A multiple logistic regression model was used and adjusted for age, sex, and current smoking. RESULTS: In total we included 1009 subjects, 105 cases with schizophrenia (10.4%) and 904 controls (89.6%). The mean suPAR values were 4.01 ng/ml (SD = 1.43) for the cases vs 1.91 ng/ml (SD = 1.35) for the controls (P < .001). Multiple logistic regression with odds ratio (OR) for suPAR levels >4.0 ng/ml yielded: schizophrenia, OR: 46.15 95% CI 22.69-93.87, P < .001; age, OR: 1.02 95% CI 0.99-1.02, P = .15; male sex, OR: 0.70 95% CI 0.35-1.36, P = .29; and current smoking, OR: 3.51 95% CI 1.78-6.94, P < .001. CONCLUSIONS: Patients with schizophrenia had significantly higher suPAR levels than healthy controls. Further studies are warranted to clarify if elevated suPAR levels are involved in the pathophysiology of schizophrenia and/or the increased mortality found in patients with schizophrenia.

[Scrotal Paget's disease].

A patient with extramammary Paget's disease (EMPD) had a plaque of the scrotum surgically removed. Histology and immunohistochemistry was consistent with primary EMPD. EMPD is a rare intraepidermal neoplasia mostly confined to regions of the skin with apocrine sweat glands. Clinical features include red plaques, which often will be mistakenly diagnosed as an infection or a rash. The treatment is surgical.