Diagnosis of rare entity CD138 negative plasma cell multiple myeloma: the synergy between laboratory and clinician makes the difference.

Plasma cell multiple myeloma (MM) is a multiform clinical entity characterized by different laboratory hallmarks. This case shows a rare entity of plasma cell myeloma: the entire plasma cell population lack the CD138 expression. In this case, a careful analysis of laboratory finding, particular flow cytometry gating strategies and the use of other ancillary laboratory tests, guide the clinicians to correct diagnosis. The correct evaluation of pre-analytical phase and the correct gating strategy are the necessary conditions to produce robust and solid flow cytometric results. The diagnostic implications of CD138-negative plasma cell are strictly linked to stem cell-like clonogenic features, such as possible more aggressive clinical behaviour and increasing probability of chemotherapy resistance. At this time, clinical laboratory remains the main reference point to MM diagnosis.

High intratumoral plasma cells content in primary prostate cancer defines a subset of tumors with potential susceptibility to immune-based treatments.

BACKGROUND: Data on advanced prostate cancer (PCa) suggest more prior systemic therapies might reduce tumor immune responsiveness. In treatment-naïve primary PCa, recent work correlated intratumoral plasma cell content with enhanced tumor immune-responsiveness. We sought to identify features of localized PCa at a high risk of recurrence following local treatment with high plasma cell content to help focus future immune-based neoadjuvant trials. METHODS: We performed retrospective analyses of molecular profiles from three independent cohorts of over 1300 prostate tumors. We used Wilcoxon Rank Sum to compare molecular pathways between tumors with high and low intratumoral plasma cell content and multivariable Cox proportional hazards regression analyses to assess metastasis-free survival. RESULTS: We validated an expression-based signature for intratumoral plasma cell content in 113 primary prostate tumors with both RNA-expression data and digital image quantification of CD138+ cells (plasma cell marker) based on immunohistochemisty. The signature showed castration-resistant tumors (n = 101) with more prior systemic therapies contained lower plasma cell content. In high-grade primary PCa, tumors with high plasma cell content were associated with increased predicted response to immunotherapy and decreased response to androgen-deprivation therapy. Master regulator analyses identified upregulated transcription factors implicated in immune (e.g. SKAP1, IL-16, and HCLS1), and B-cell activity (e.g. VAV1, SP140, and FLI-1) in plasma cell-high tumors. Master regulators overactivated in tumors with low plasma cell content were associated with shorter metastasis-free survival following radical prostatectomy. CONCLUSIONS: Markers of plasma cell activity might be leveraged to augment clinical trial targeting and selection and better understand the potential for immune-based treatments in patients with PCa at a high risk of recurrence following local treatment.

MUM-1 immunohistochemistry has high accuracy and reliability in the diagnosis of chronic endometritis: a multi-centre comparative study with CD-138 immunostaining.

PURPOSE: The current gold standard for chronic endometritis (CE) diagnosis is immunohistochemistry (IHC) for CD-138. However, IHC for CD-138 is not exempt from diagnostic limitations. The aim of our study was to evaluate the reliability and accuracy of MUM-1 IHC, as compared with CD-138. METHODS: This is a multi-centre, retrospective, observational study, which included three tertiary hysteroscopic centres in university teaching hospitals. One hundred ninety-three consecutive women of reproductive age were referred to our hysteroscopy services due to infertility, recurrent miscarriage, abnormal uterine bleeding, endometrial polyps or myomas. All women underwent hysteroscopy plus endometrial biopsy. Endometrial samples were analysed through histology, CD138 and MUM-1 IHC. The primary outcome was to evaluate the diagnostic accuracy of MUM-1 IHC for CE, as compared with CD-138 IHC. RESULTS: Sensitivity and specificity of CD-138 and MUM-1 IHC were respectively 89.13%, 79.59% versus 93.48% and 85.03%. The overall diagnostic accuracy of MUM-1 and CD-138 IHC were similar (AUC = 0.893 vs AUC = 0.844). The intercorrelation coefficient for single measurements was high between the two techniques (ICC = 0.831, 0.761-0.881 95%CI). However, among CE positive women, MUM-1 allowed the identification of higher number of plasma cells/hpf than CD-138 (6.50 [SD 4.80] vs 5.05 [SD 3.37]; p = 0.017). Additionally, MUM-1 showed a higher inter-observer agreement as compared to CD-138. CONCLUSION: IHC for MUM-1 and CD-138 showed a similar accuracy for detecting endometrial stromal plasma cells. Notably, MUM-1 showed higher reliability in the paired comparison of the individual samples than CD-138. Thus, MUM-1 may represent a novel, promising add-on technique for the diagnosis of CE.

Single Institutional Experience on Orbital Inflammatory Pseudotumor: Diagnostic and Management Challenge.

AIMS: Orbital inflammatory pseudotumor is considered a non-neoplastic inflammatory process. The finding of clonality of B or T-cell receptors in cases pathologically diagnosed as orbital inflammatory pseudotumor has unknown clinicopathologic significance. We sought to investigate potential B and T-cell clonality and concomitant diseases in cases pathologically diagnosed as orbital inflammatory pseudotumor. METHODS: Cases diagnosed as orbital inflammatory pseudotumor at our institution were retrospectively analyzed. Hematoxylin and eosinstained slides, immunohistochemically stained slides and polymerase chain reactions on cell block material for the investigation of clonality of B and T-cell receptors were evaluated, to confirm the diagnosis and investigate the prevalence of concomitant diseases. RESULTS: A total of 13 cases showing characteristic histopathologic features of orbital inflammatory pseudotumor were identified. CD138, IgG, and IgG4 showed varying numbers of plasma cells in each case, with 5 cases (5/13, 38%) exhibiting relative increase in the presence of IgG4 plasma cells. However, no cases showed diagnostic findings of IgG4-related disease (IgG4-RD). polymerase chain reactions analysis showed clonal B-cell populations in 2 cases (2/13, 15%). No cases showed anaplastic lymphoma kinase expression by immunohistochemistry. There were no clinical reports of progression to lymphoma or development of systemic IgG4-RD in any of the patients (average follow-up of 300 days), with 38% of patients showing systemic autoimmune conditions. CONCLUSION: A small but significant percentage of typical orbital inflammatory pseudotumor on histology showed B-cell clonality on polymerase chain reactions analysis of B-cell receptors, or features suggestive, but not diagnostic of IgG4-RD. Close follow-up of these patients to identify development of lymphoma, systemic IgG4-RD, or other rheumatologic conditions may be clinically warranted.

Novel predictive biomarkers for acute injury superimposed on chronic kidney disease / Novedosos biomarcadores predictivos para lesiones agudas superpuestas a una enfermedad renal crónica

INTRODUCTION AND OBJECTIVES: Chronic kidney disease (CKD) is a risk factor for the development of acute kidney injury (AKI). Recent studies have revealed numerous biomarkers eligible for AKI prediction. However, the expression and performance of AKI biomarkers in acute injury superimposed on preexisting CKD (AonC) remain elusive. The aim of this study was to evaluate whether biomarkers which robustly expressed in acute kidney injury could predict acute injury based on CKD. MATERIALS AND METHODS: Mice were classified into cohorts: AKI, CKD, AonC and sham. The AonC model mice were subjected to renal bilateral ischemia/reperfusion (I/R) injury fourteen days after intraperitoneally administrated with 20 mg/kg aristolochic acid. Severity of acute ischemic injury was stratified by clamping the dissected bilateral renal arteries with non-traumatic microvascular clips for 20 or 35 min. The AKI mice were induced with renal bilateral I/R injury and CKD mice were crafted with 20mg/kg aristolochic acid administrated intraperitoneally. Histology, genetic and protein expression of biomarkers were measured in three cohorts. RESULTS: We found that serum creatinine dramatically increased in severe (sAonC) but not in moderate (mAonC) injury mice. Upregulation of Kidney injury molecule-1 (KIM-1) mRNA, tissue inhibitor of metalloproteinase-2 (TIMP-2), Syndecan-1 (SDC-1) mRNA and insulin-like growth factor binding protein-7 (IGFBP7) protein indicated the onset of mAonC. An increase in neutrophil gelatinase-associated lipocalin (NGAL), rhomboid-like protein 2 (RHBDL2), Syndecan-1 (SDC-1) mRNA and protein, and a decrease in IGFBP7 protein were associated with sAonC. CONCLUSIONS: Our study revealed the variational expression of AKI biomarkers in AonC kidneys, and uncovered IGFBP7 protein can be used as a sensitive biomarker to predict and differentiate AonC severity. The performance of RHBDL2 and SDC-1 in predicting severe AonC was promising, providing new biomarkers for predicting AonC

INTRODUCCIÓN Y OBJETIVOS: La enfermedad renal crónica (ERC) es un factor de riesgo para el desarrollo de una lesión renal aguda (LRA). Estudios recientes han revelado numerosos biomarcadores para la predicción de LRA. No obstante, la expresión y el rendimiento de los biomarcadores de LRA en lesiones agudas superpuestas a una ERC preexistente (AonC, en inglés) siguen siendo imprecisos. El objetivo de este estudio fue evaluar si los biomarcadores que se encuentran muy expresados en la lesión renal aguda podrían predecir una lesión aguda superpuesta a una ERC. MATERIALES Y MÉTODOS: Se dividieron ratones en cohortes (LRA, ERC, AonC y grupo de referencia). A los ratones del modelo de AonC se les indujo una lesión renal bilateral por isquemia/reperfusión (I/R) 14 días después de la administración intraperitoneal de 20 mg/kg de ácido artistolóquico. La gravedad de la lesión isquémica aguda se estratificó pinzando las arterias renales bilaterales diseccionadas con horquillas microvasculares no traumáticas durante 20 o 35 min. A los ratones de LRA se les indujo una lesión renal bilateral por I/R y a los ratones de ERC se les administraron 20mg/kg de ácido artistolóquico por vía intraperitoneal. Se determinaron la histología, la genética y la expresión de proteínas en las tres cohortes. RESULTADOS: Observamos que la creatinina sérica aumentaba drásticamente en los ratones con lesiones graves (AonCg) pero no en aquellos con lesiones moderadas (AonCm) El aumento del ARNm de la molécula1 de lesión renal (KIM-1), del inhibidor tisular de metaloproteinasas 2 (TIMP-2), del ARNm de sindecán 1 (SDC-1) y de la proteína de unión al factor de crecimiento insulinoide 7 (IGFBP7) fue indicativo de aparición de AonCm. El incremento de la lipocalina asociada a la gelatinasa de neutrófilos (NGAL), la proteína romboidal 2 (RHBDL2) y el ARNm y la proteína de sindecán 1 (SDC-1), así como la reducción de la proteína IGFBP7, se asociaron a una AonCg. CONCLUSIONES: Nuestro estudio mostró la variación de la expresión de los biomarcadores de LRA en riñones con AonC y descubrió que la proteína IGFBP7 puede emplearse como biomarcador sensible para la predicción y la diferenciación de la gravedad de la AonC. El rendimiento de RHBDL2 y SDC-1 en la predicción de AonC graves resultó prometedor, lo que ofrece nuevos biomarcadores para la predicción de AonC

Endothelial damage in septic shock patients as evidenced by circulating syndecan-1, sphingosine-1-phosphate and soluble VE-cadherin: a substudy of ALBIOS.

BACKGROUND: Septic shock is characterized by breakdown of the endothelial glycocalyx and endothelial damage, contributing to fluid extravasation, organ failure and death. Albumin has shown benefit in septic shock patients. Our aims were: (1) to identify the relations between circulating levels of syndecan-1 (SYN-1), sphingosine-1-phosphate (S1P) (endothelial glycocalyx), and VE-cadherin (endothelial cell junctions), severity of the disease, and survival; (2) to evaluate the effects of albumin supplementation on endothelial dysfunction in patients with septic shock. METHODS: This was a retrospective analysis of a multicenter randomized clinical trial on albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis Trial, ALBIOS). Concentrations of SYN-1, S1P, soluble VE-cadherin and other biomarkers were measured on days 1, 2 and 7 in 375 patients with septic shock surviving up to 7 days after randomization. RESULTS: Plasma concentrations of SYN-1 and VE-cadherin rose significantly over 7 days. SYN-1 and VE-cadherin were elevated in patients with organ failure, and S1P levels were lower. SYN-1 and VE-cadherin were independently associated with renal replacement therapy requirement during ICU stay, but only SYN-1 predicted its new occurrence. Both SYN-1 and S1P, but not VE-cadherin, predicted incident coagulation failure. Only SYN-1 independently predicted 90-day mortality. Albumin significantly reduced VE-cadherin, by 9.5% (p = 0.003) at all three time points. CONCLUSION: Circulating components of the endothelial glycocalyx and of the endothelial cell junctions provide insights into severity and progression of septic shock, with special focus on incident coagulation and renal failure. Albumin supplementation lowered circulating VE-cadherin consistently over time. CLINICAL TRIAL REGISTRATION: ALBIOS ClinicalTrials.gov number NCT00707122.

Angiopoietin-2 outperforms other endothelial biomarkers associated with severe acute kidney injury in patients with severe sepsis and respiratory failure.

BACKGROUND: Endothelial dysfunction and injury is a major pathophysiologic feature of sepsis. Sepsis is also the most frequent cause of acute kidney injury (AKI) in critically ill patients. Though most studies of AKI in sepsis have focused on tubular epithelial injury, the role of endothelial dysfunction and injury is less well studied. The goal of this study was first to investigate whether endothelial dysfunction and injury biomarkers were associated with severe AKI in sepsis patients. The second goal was to determine the best performing biomarker for severe AKI and whether this biomarker was associated with severe AKI across different etiologies of sepsis and clinical outcomes. METHODS: We studied adults with severe sepsis and acute respiratory failure (ARF) enrolled in the prospective observational Validating Acute Lung Injury markers for Diagnosis (VALID) study. Plasma endothelial dysfunction and injury biomarkers, including angiopoietin-2, soluble vascular endothelial cadherin (sVE-cadherin), endocan and syndecan-1, were measured at study enrollment. Primary analysis focused on the association between endothelial biomarker levels with severe AKI (defined as Kidney Disease: Improving Global Outcomes [KDIGO] AKI stage 2 or 3), other organ dysfunctions (defined by Brussels organ failure scores), and comparison of pulmonary versus non-pulmonary sepsis. RESULTS: Among 228 sepsis patients enrolled, 141 developed severe AKI. Plasma levels of angiopoietin-2, endocan, sVE-cadherin, and syndecan-1 were significantly higher in sepsis patients with severe AKI compared to those without severe AKI. Among four endothelial biomarkers, only angiopoietin-2 was independently associated with severe AKI (odds ratio 6.07 per log increase, 95% CI 2.34-15.78, p < 0.001). Plasma angiopoietin-2 levels by quartile were significantly higher in sepsis patients with hepatic, coagulation, and circulatory failure. Plasma angiopoietin-2 levels were also significantly higher in patients with non-pulmonary sepsis compared to subjects with pulmonary sepsis. CONCLUSION: Among four biomarkers of endothelial dysfunction and injury, angiopoietin-2 had the most robust independent association with development of severe AKI in patients with severe sepsis and ARF. Plasma angiopoietin-2 levels were also associated with other organ dysfunctions, non-pulmonary sepsis, and death. These findings highlight the importance of early endothelial dysfunction and injury in the pathogenesis of sepsis-induced AKI.

Effect of volatile and total intravenous anesthesia on syndecan-1 shedding after minimally invasive gastrectomy: a randomized trial.

This study aimed to compare the effects of volatile anesthesia and total intravenous anesthesia (TIVA) on syndecan-1 shedding in patients with gastric cancer undergoing minimally invasive gastrectomy. Patients were randomly assigned to either the Volatile (n = 68) or the TIVA (n = 68) group. Anesthesia was maintained with sevoflurane/remifentanil or propofol/remifentanil in the Volatile and TIVA groups, respectively. Serum syndecan-1 was evaluated at pre-operation, end of operation, and postoperative day (POD) 1. Inflammatory markers including white blood cell (WBC) count, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), were also measured at pre-operation, end of operation, and POD 1, 2, 3, and 5. The TIVA group showed significantly lower levels of syndecan-1 at the end of the operation compared to the Volatile group; however, no difference was seen between the groups at POD 1. The WBC count and NLR were significantly lower in the TIVA group at the end of the operation than the Volatile group, but there were no differences between the groups at POD 1, 2, 3, and 5. CRP levels were similar between the groups at all time points. In conclusion, despite TIVA being superior to volatile anesthesia in protecting endothelial glycocalyx during the operation, both did not prevent postoperative syndecan-1 shedding after gastrectomy.Clinical trial registration number: NCT04183296 (ClinicalTrial.gov, 03/12/2019).

Multiple myeloma with CD138 changed from positive to negative: A case report.

BACKGROUND: Multiple myeloma (MM) is a common malignant disease of the blood system, caused by the neoplastic proliferation of plasma cells that accumulate in bone marrow (BM). Here, we report a case of MM patient with CD138 marker changed from positive to negative. METHODS: BM and peripheral blood samples from a 48-year-old patient with MM were examined and analyzed by conventional morphology, flow cytometry, and immunodetection. RESULTS: Imaging examination and clinical manifestations fulfilled criteria for MM. On the first hospitalization, flow cytometry showed that the cells were CD138+ /CD38+ /CD19- /CD56+ . However, on the fifth hospitalization, flow cytometry revealed that the cells were CD138- /CD38+ /CD19- /CD56+ . CONCLUSIONS: MM is diagnosed on imaging and clinical manifestations, immunophenotype of flow cytometry is also an important method of diagnosing MM. However, the discovery of atypical immunophenotypes cannot prevent the diagnosis of MM, even provide a clue of disease progression.

Virus-infected peripheral blood plasmablasts in a patient with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral hemorrhagic disease with a high fatality rate. It is caused by the SFTS virus and is endemic in East Asian countries such as China, South Korea, and Japan. Previous studies have shown that plasmablasts appear transiently in peripheral blood during the acute phase of SFTS, but do not specify the characteristics of these plasmablasts. In this report, we describe the features of peripheral blood plasmablasts in a patient with SFTS. Immunohistochemical and immunofluorescence staining detected a small number of atypical lymphocytes expressing the SFTS virus antigen among peripheral leukocytes in a blood sample. The phenotype of the virus-infected cells was CD27+, CD38+, MUM1+, and CD138+, which is consistent with that of plasmablasts. This novel study demonstrates that plasmablasts in the peripheral blood of patients with SFTS are targets of the SFTS virus.

The cut-offs for kappa/lambda ratio in bone marrow immunohistochemistry for the diagnosis of multiple myeloma.

Objective: The previously reported kappa/lambda ratio cut-offs for plasma cell clonality by immunohistochemistry were in different values. This study aimed to identify the cut-offs with the highest accuracy for the diagnosis of multiple myeloma. Methods: Bone marrow specimens consecutively recruited between January 2011 and March 2019. The patients were at least 18 years old with clinical suspicion of multiple myeloma and had bone marrow plasma cell ≥10% by CD138 immunohistochemistry. The index test was immunohistochemical stains for plasma cell kappa/lambda ratio. The reference standard to classify as multiple myeloma required meeting any of the following (1) kappa/lambda ratio ≤1/16 or ≥16, (2) abnormal plasma cell morphology, and (3) monoclonal immunoglobulin. Results: From 147 specimens (70 multiple myelomas and 77 reactive plasmacytosis), our cut-offs kappa/lambda ratio for light chain restriction at ≤1/7 or ≥9 yielded an area under the receiver operating characteristic curve of 1.0000 while ≤1/16 or ≥16 yielded 0.9643 (p-value 0.0212). Conclusion: The cut-offs for kappa/lambda ratio at ≤1/7 or ≥9 for diagnosis of multiple myeloma yielded the highest diagnostic accuracy. The suggested cut-offs could be of potential value in resource-limited laboratories.

The impact of bone marrow fibrosis and JAK2 expression on clinical outcomes in patients with newly diagnosed multiple myeloma treated with immunomodulatory agents and/or proteasome inhibitors.

We determined the impact of bone marrow fibrosis (BMF) on the clinical outcomes of newly diagnosed multiple myeloma (NDMM) patients in the current era of myeloma therapy. A total of 393 MM patients were included in the final analysis. The median followup was 83 months (range: 3.9 to 212 months). BMF was noted in 122 (48.2%) evaluable patients. Median progression free survival (PFS) in patients without BMF was 30.2 (95% CI: 24.7-38.0) months, and 21.1 (95% CI: 18.8-27.5) months in patients with BMF present (P = .024). Median overall survival (OS) was 61.2 (95% CI: 51.5-81.2) months in patients without BMF, and 45.1 (95% CI: 38.7-57.0) months in patients with BMF (P = .0048). A subset of 99 patients had their bone marrow biopsies stained for JAK1 and JAK2 by immunohistochemistry. Of these samples 67 (67.7%) patients had detectable JAK2 expression predominantly noted on bone marrow megakaryocytes. JAK2 expression correlated with myeloma disease stage (P = .0071). Our study represents the largest dataset to date examining the association of BMF with prognosis in the era of novel therapies and widespread use of hematopoietic stem cell transplant (HSCT). Our data suggest that MM patients with BMF (particularly those with extensive BMF) have a poorer prognosis even when treated with immunomodulatory agents and proteasome inhibitors.

Hypertonic sodium lactate improves microcirculation, cardiac function, and inflammation in a rat model of sepsis.

BACKGROUND: Hypertonic sodium lactate (HSL) may be of interest during inflammation. We aimed to evaluate its effects during experimental sepsis in rats (cecal ligation and puncture (CLP)). METHODS: Three groups were analyzed (n = 10/group): sham, CLP-NaCl 0.9%, and CLP-HSL (2.5 mL/kg/h of fluids for 18 h after CLP). Mesenteric microcirculation, echocardiography, cytokines, and biochemical parameters were evaluated. Two additional experiments were performed for capillary leakage (Evans blue, n = 5/group) and cardiac hemodynamics (n = 7/group). RESULTS: HSL improved mesenteric microcirculation (CLP-HSL 736 [407-879] vs. CLP-NaCl 241 [209-391] UI/pixel, p = 0.0006), cardiac output (0.34 [0.28-0.43] vs. 0.14 [0.10-0.18] mL/min/g, p < 0.0001), and left ventricular fractional shortening (55 [46-73] vs. 39 [33-52] %, p = 0.009). HSL also raised dP/dtmax slope (6.3 [3.3-12.1] vs. 2.7 [2.0-3.9] 103 mmHg/s, p = 0.04), lowered left ventricular end-diastolic pressure-volume relation (1.9 [1.1-2.3] vs. 3.0 [2.2-3.7] RVU/mmHg, p = 0.005), and reduced Evans blue diffusion in the gut (37 [31-43] vs. 113 [63-142], p = 0.03), the lung (108 [82-174] vs. 273 [222-445], p = 0.006), and the liver (24 [14-37] vs. 70 [50-89] ng EB/mg, p = 0.04). Lactate and 3-hydroxybutyrate were higher in CLP-HSL (6.03 [3.08-10.30] vs. 3.19 [2.42-5.11] mmol/L, p = 0.04; 400 [174-626] vs. 189 [130-301] µmol/L, p = 0.03). Plasma cytokines were reduced in HSL (IL-1ß, 172 [119-446] vs. 928 [245-1470] pg/mL, p = 0.004; TNFα, 17.9 [12.5-50.3] vs. 53.9 [30.8-85.6] pg/mL, p = 0.005; IL-10, 352 [267-912] vs. 905 [723-1243] pg/mL) as well as plasma VEGF-A (198 [185-250] vs. 261 [250-269] pg/mL, p = 0.009). CONCLUSIONS: Hypertonic sodium lactate fluid protects against cardiac dysfunction, mesenteric microcirculation alteration, and capillary leakage during sepsis and simultaneously reduces inflammation and enhances ketone bodies.

A New Hysteroscopic Scoring System for Diagnosing Chronic Endometritis.

STUDY OBJECTIVE: To develop a new hysteroscopic morphologic scoring system to diagnose chronic endometritis (CE). DESIGN: Prospective study. SETTING: Medical hysteroscopy office. PATIENTS: In total, 320 patients underwent hysteroscopy, dilation and curettage, and endometrial biopsies from February 2017 to June 2018 with the intention of undergoing assisted reproductive technology treatment because of infertility or recurrent miscarriage. INTERVENTIONS: All patients underwent hysteroscopy, dilation and curettage, and endometrial biopsies for histologic examination and were classified according to the new hysteroscopic morphologic scoring system. MEASUREMENTS AND MAIN RESULTS: Of the 320 patients, 164 received a diagnosis of CE by histology (group A), whereas 156 patients were found not to have CE (group B). A total of 116 patients were diagnosed by our hysteroscopy scoring system to have CE, and 204 patients did not have CE. The scoring system showed a sensitivity and specificity of 62.8% and 91.7%, respectively. The positive predictive values and negative predictive values were 88.8% and 70.1%, respectively. Receiver operating characteristic analysis showed a cutoff value of >2 and an area under the curve of 0.823. Hysteroscopic and histologic grading showed moderate agreement (κ index = 0.529). CONCLUSION: Our hysteroscopic scoring system has a high sensitivity and specificity for CE; it is hoped that its use can reduce interobserver variability. Future clinical studies are warranted to confirm the validity and clinical applicability of the proposed hysteroscopic morphologic scoring system for CE.

CD14+ CD16+ monocytes are involved in daratumumab-mediated myeloma cells killing and in anti-CD47 therapeutic strategy.

A deep elucidation of the mechanisms of action of anti-CD38 monoclonal antibodies (mAbs), such as daratumumab (DARA), is required to identify patients with multiple myeloma (MM) who are more responsive to this treatment. In the present study, an autologous ex vivo approach was established, focussing on the role of the monocytes in the anti CD38-mediated killing of MM cells. In bone marrow (BM) samples from 29 patients with MM, we found that the ratio between monocytes (CD14+ ) and MM cells (CD138+ ) influences the response to DARA. Further, the exposure of the BM samples to DARA is followed by the formation of a CD138+ CD14+ double-positive (DP) population, that quantitatively correlates with the anti-MM cells killing. These effects were dependent on the presence of a CD14+ CD16+ monocyte subset and on high CD16 expression levels. Lastly, the addition of a mAb neutralising the CD47/signal-regulatory protein α (SIRPα) axis was able to increase the killing mediated by DARA. The effects were observed only in coincidence with high CD14+ :CD138+ ratio, with a significant presence of the DP population and were correlated with CD16 expression. In conclusion, the present study underlines the critical role of the CD16+ monocytes in DARA anti-MM killing effects and gives a rationale to test the combination of an anti-CD47 mAb with anti-CD38 mAbs.

Rare Breast Carcinoma with Paradoxical Plasma Cell Immunoprofile: A Case Report.

Plasma cell features are encountered in a variety of non-plasma cell neoplasias, especially carcinomas of a discohesive type, such as those occurring in the digestive tract and breast. Lobular carcinomas of the breast present themselves in a variety of architectural patterns and many cell morphologies, including plasmacytoid types. A matching plasma cell phenotype is sometimes an associated feature. We report a case of a moderate grade invasive lobular carcinoma with focal plasmacytoid morphology and aberrant expression of plasma cell markers in a patient previously diagnosed with multiple myeloma. Paradoxical plasma cell immunoprofiles can be encountered in many malignancies, causing serious diagnostic problems, even more so with those occurring in discohesive carcinomas in multiple myeloma patients.

Plasma and Urinary Glycosaminoglycans as Evidence for Endotheliopathy in a Swine Burn Model.

BACKGROUND: The endothelial glycocalyx controls vascular permeability, cellular signaling, blood-endothelial cell adhesion, extravasation, and transmission of shear stress signals. Burn injury compromises integrity of this layer increasing vascular permeability, which is further exacerbated by large volumes of (intravenous) crystalloids. We have shown that enteral resuscitation is able to reverse burn-induced acute kidney injury (AKI), and herein, we present a follow-up examination of the integrity of the glycocalyx layer and its relationship with renal dysfunction after burn injury. MATERIALS AND METHODS: Anesthetized Yorkshire pigs sustained 40% total body surface area full-thickness contact burns and recovered in metabolic cages for one of three treatments: no fluids (oral or intravenous); (n = 6), ad libitum water (n = 6), or volume-matched oral rehydration solution (ORS; n = 6) for 48 h. Urine and blood were collected at baseline (BL), 6, 12, 24, 32, and 48 h after burn at which point kidneys were harvested. RESULTS: In no fluid and water groups (but not ORS), plasma levels of glycosaminoglycans (GAGs) were elevated after burn (P ≤ 0.031). Syndecan-1 was elevated by 6 h after burn in all animals, but levels declined by 24 h with enteral fluids. Urinary GAGs in the no-fluid group were elevated after burn. No differences among treatments were detected in syndecan-1 levels, or glomerular lectin within the kidney. CONCLUSIONS: Collectively, these data demonstrate that ORS prevented increases in circulating GAGs. Furthermore, an inexpensive and simple method for detecting GAGs provides a sensitive measure of endotheliopathy after burn.

Endometrial CD138 count appears to be a negative prognostic indicator for patients who have experienced previous embryo transfer failure.

OBJECTIVE: To explore the predictive value of endometrial CD138 expression in the natural cycle preceding frozen embryo transfer in patients with normal endometrial dating and histopathologic features, who previously failed the transfer of two high-quality fresh embryos. DESIGN: Retrospective analysis. SETTING: University-affiliated hospital. PATIENT(S): Women with normal endometrial dating and histopathologic features who previously failed the transfer of two high-quality fresh embryos, and who then underwent an endometrial scratching operation preceding a natural cycle. INTERVENTION(S): Paraffin-embedded endometrial samples cut into sections for immunohistochemistry staining of CD138 (syndecan-1) expression, then clinical information for these patients reviewed and analyzed. MAIN OUTCOME MEASURE(S): Clinical rates of pregnancy and implantation. RESULT(S): A total of 141 women met the inclusion criteria. Of these patients, about 31.2% (44 of 141) were positive for CD138 expression, with CD138 counts ranging from 0 to 33. Receiver operating characteristic (ROC) curves were analyzed to determine whether the number of cells expressing CD138 (CD138+ cells) predicted a successful pregnancy. The areas under the ROC curves based on CD138+ cell density and CD138+ cell count were 0.660 and 0.658, respectively. The clinical pregnancy and embryo implantation rates in patients not expressing CD138 (80.04% and 64.9%, respectively) were statistically significantly higher than rates in CD138+ patients (52.7% and 46.8%, respectively). In addition, the higher the number of cells expressing CD138, the worse the outcome of the pregnancy. Finally, clinical data showed that free pelvic fluid on the day of endometrial sampling (identified using transvaginal ultrasound) might be a risk factor for CD138 expression. CONCLUSION(S): Endometrial CD138+ count might be a valuable marker predicting pregnancy outcomes after frozen embryo transfer in patients with normal endometrial dating and histopathologic features who previously failed the transfer of two high-quality fresh embryos.