NEMO/NF-κB signaling functions as a double-edged sword in PanIN formation versus progression to pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is marked by a dismal survival rate, lacking effective therapeutics due to its aggressive growth, late-stage diagnosis, and chemotherapy resistance. Despite debates on NF-κB targeting for PDAC treatment, no successful approach has emerged. METHODS: To elucidate the role of NF-κB, we ablated NF-κB essential modulator (NEMO), critical for conventional NF-κB signaling, in the pancreata of mice that develop precancerous lesions (KC mouse model). Secretagogue-induced pancreatitis by cerulein injections was utilized to promote inflammation and accelerate PDAC development. RESULTS: NEMO deletion reduced fibrosis and inflammation in young KC mice, resulting in fewer pancreatic intraepithelial neoplasias (PanINs) at later stages. Paradoxically, however, NEMO deletion accelerated the progression of these fewer PanINs to PDAC and reduced median lifespan. Further, analysis of tissue microarrays from human PDAC sections highlighted the correlation between reduced NEMO expression in neoplastic cells and poorer prognosis, supporting our observation in mice. Mechanistically, NEMO deletion impeded oncogene-induced senescence (OIS), which is normally active in low-grade PanINs. This blockage resulted in fewer senescence-associated secretory phenotype (SASP) factors, reducing inflammation. However, blocked OIS fostered replication stress and DNA damage accumulation which accelerated PanIN progression to PDAC. Finally, treatment with the DNA damage-inducing reagent etoposide resulted in elevated cell death in NEMO-ablated PDAC cells compared to their NEMO-competent counterparts, indicative of a synthetic lethality paradigm. CONCLUSIONS: NEMO exhibited both oncogenic and tumor-suppressive properties during PDAC development. Caution is suggested in therapeutic interventions targeting NF-κB, which may be detrimental during PanIN progression but beneficial post-PDAC development.

DNA methylation-associated allelic inactivation regulates Keratin 19 gene expression during pancreatic development and carcinogenesis.

Within the pancreas, Keratin 19 (KRT19) labels the ductal lineage and is a determinant of pancreatic ductal adenocarcinoma (PDAC). To investigate KRT19 expression dynamics, we developed a human pluripotent stem cell (PSC)-based KRT19-mCherry reporter system in different genetic backgrounds to monitor KRT19 expression from its endogenous gene locus. A differentiation protocol to generate mature pancreatic duct-like organoids was applied. While KRT19/mCherry expression became evident at the early endoderm stage, mCherry signal was present in nearly all cells at the pancreatic endoderm (PE) and pancreatic progenitor (PP) stages. Interestingly, despite homogenous KRT19 expression, mCherry positivity dropped to 50% after ductal maturation, indicating a permanent switch from biallelic to monoallelic expression. DNA methylation profiling separated the distinct differentiation intermediates, with site-specific DNA methylation patterns occurring at the KRT19 locus during ductal maturation. Accordingly, the monoallelic switch was partially reverted upon treatment with a DNA-methyltransferase inhibitor. In human PDAC cohorts, high KRT19 levels correlate with low locus methylation and decreased survival. At the same time, activation of oncogenic KRASG12D signalling in our reporter system reversed monoallelic back to biallelic KRT19 expression in pancreatic duct-like organoids. Allelic reactivation was also detected in single-cell transcriptomes of human PDACs, which further revealed a positive correlation between KRT19 and KRAS expression. Accordingly, KRAS mutant PDACs had higher KRT19 mRNA but lower KRT19 gene locus DNA methylation than wildtype counterparts. KRT19 protein was additionally detected in plasma of PDAC patients, with higher concentrations correlating with shorter progression-free survival in gemcitabine/nabPaclitaxel-treated and opposing trends in FOLFIRINOX-treated patients. Apart from being an important pancreatic ductal lineage marker, KRT19 appears tightly controlled via a switch from biallelic to monoallelic expression during ductal lineage entry and is aberrantly expressed after oncogenic KRASG12D expression, indicating a role in PDAC development and malignancy. Soluble KRT19 might serve as a relevant biomarker to stratify treatment. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Mucins Shed from the Laminated Layer in Cystic Echinococcosis Are Captured by Kupffer Cells via the Lectin Receptor Clec4F.

Cystic echinococcosis is caused by the larval stages (hydatids) of cestode parasites belonging to the species cluster Echinococcus granulosus sensu lato, with E. granulosus sensu stricto being the main infecting species. Hydatids are bladderlike structures that attain large sizes within various internal organs of livestock ungulates and humans. Hydatids are protected by the massive acellular laminated layer (LL), composed mainly of mucins. Parasite growth requires LL turnover, and abundant LL-derived particles are found at infection sites in infected humans, raising the question of how LL materials are dealt with by the hosts. In this article, we show that E. granulosus sensu stricto LL mucins injected into mice are taken up by Kupffer cells, the liver macrophages exposed to the vascular space. This uptake is largely dependent on the intact mucin glycans and on Clec4F, a C-type lectin receptor which, in rodents, is selectively expressed in Kupffer cells. This uptake mechanism operates on mucins injected both in soluble form intravenously (i.v.) and in particulate form intraperitoneally (i.p.). In mice harboring intraperitoneal infections by the same species, LL mucins were found essentially only at the infection site and in the liver, where they were taken up by Kupffer cells via Clec4F. Therefore, shed LL materials circulate in the host, and Kupffer cells can act as a sink for these materials, even when the parasite grows in sites other than the liver.

Epigenetic lockdown of CDKN1A (p21) and CDKN2A (p16) characterises the neoplastic spindle cell component of giant cell tumours of bone.

Giant cell tumour of bone (GCTB) comprises the eponymous osteoclastic multinucleated giant cells eliciting bone lysis, an H3F3A-mutated neoplastic mononucleated fibroblast-like cell population, and H3F3A wild-type mononucleated stromal cells. In this study, we characterised four new cell lines from GCTB. Furthermore, we compared the genome-wide DNA methylation profile of 13 such tumours and three further cell lines with giant cell-rich lesions comprising three H3F3B-mutated chondroblastomas, three USP6-rearranged aneurysmal bone cysts, three non-ossifying fibromas, two hyperparathyroidism-associated brown tumours as well as mesenchymal stem cells, osteoblasts, and osteoclasts. In an unsupervised analysis, we delineated GCTB and chondroblastomas from the other analysed tumour entities. Using comparative methylation analysis, we demonstrated that the methylation pattern of the cell lines approximately equals that of H3F3A-mutated stromal cells in tissue. These patterns more resemble that of osteoblasts than that of mesenchymal stem cells, which argues for the osteoblast as the cell of origin of giant cell tumours of bone. Using enrichment analysis, we detected distinct hypermethylated clusters containing histone and collagen genes as well as target genes of the tumour suppressor p53. We found that the promotor regions of CDKN1A, CDKN2A, and IGFBP3 are methylated more strongly in GCTB than in the other giant cell-containing lesions, mesenchymal stem cells, osteoblasts, and osteoclasts (p < 0.001). This hypermethylation correlates with the lower gene expression at the mRNA level for these three genes in the cell lines, the lack of p16 and p21 in these cell lines, and the lower expression of p16 and p21 in GCTB. Overall, our analysis reveals characteristic DNA methylation patterns of giant cell tumours of bone and chondroblastomas and shows that cell lines of giant cell tumours of bone are a valid model for further analysis of H3F3A-mutated tumour cells. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Age- and sex-related variations of individual retinal layer thickness in the foveal center of healthy eyes.

Alterations of the visual function during life are associated with changes in the morphological parameters of the outer retinal layers of the fovea. We evaluated age- and sex-related variations of the mean thicknesses of the different retinal layers at the central foveola which provides the maximal visual acuity. The vertical expansions of the following structures were measured on spectral-domain optical coherence tomographic images of 2944 healthy eyes of 1990 subjects with ages between 5 and 85 years: the total thickness of the retinal tissue, the thickness of the retinal pigment epithelium, the lengths of photoreceptors (receptor segments), photoreceptor outer segments (POS), and photoreceptor inner segments (PIS), and the thicknesses of the ellipsoid zone (EZ), myoid zone (MZ), external limiting membrane, outer nuclear layer, Henle fiber layer, and the horizontal layer of the Müller cell cone. We found diverse morphologies of the central photoreceptor layer with different thicknesses of the EZ and interdigitation zone lines. The mean total thickness of the retinal tissue at the central foveola showed three periods: it increased between 5 and about 41 years of age, displayed a plateau until about 52 years, and decreased continuously thereafter. Photoreceptors, POS, and PIS displayed their maximal mean lengths between 5 and about 36 years of age; the lengths decreased continuously between 36 and 85 years of age. Whereas the mean thickness of the EZ did not alter across the life span, the mean thickness of MZ displayed three periods: it increased between 5 and about 21 years of age, showed a plateau until about 36 years, and decreased considerably thereafter. Sex differences were observed for five parameters in eyes of subjects aging between 55 and 85 years. We suggest that the MZ thickness reflects the level of the metabolic activity of photoreceptors. The increase in the MZ thickness, likely reflecting increasing metabolic activity of photoreceptors, might contribute to the improvement of visual function in young subjects. The decrease of the MZ thickness in the fovea of elderly might reflect a decrease of the metabolic activity perhaps resulting from mitochondrial dysfunction which is known to occur in photoreceptors of aged eyes.

Temporal-spatial organ response after blast-induced experimental blunt abdominal trauma.

Abdominal trauma (AT) is of major global importance, particularly with the increased potential for civil, terroristic, and military trauma. The injury pattern and systemic consequences of blunt abdominal injuries are highly variable and frequently underestimated or even missed, and the pathomechanisms remain still poorly understood. Therefore, we investigated the temporal-spatial organ and immune response after a standardized blast-induced blunt AT. Anesthetized mice were exposed to a single blast wave centered on the epigastrium. At 2, 6, or 24 h after trauma, abdominal organ damage was assessed macroscopically, microscopically, and biochemically. A higher degree of trauma severity, determined by a reduction of the distance between the epigastrium and blast inductor, was reflected by a reduced survival rate. The hemodynamic monitoring during the first 120 min after AT revealed a decline in the mean arterial pressure within the first 80 min, whereas the heart rate remained quite stable. AT induced a systemic damage and inflammatory response, evidenced by elevated HMGB-1 and IL-6 plasma levels. The macroscopic injury pattern of the abdominal organs (while complex) was consistent, with the following frequency: liver > pancreas > spleen > left kidney > intestine > right kidney > others > lungs and was reflected by microscopic liver and pancreas damages. Plasma levels of organ dysfunction markers increased during the first 6 h after AT and subsequently declined, indicating an early, temporal impairment of the function on a multi-organ level. The established highly reproducible murine blunt AT, with time- and trauma-severity-dependent organ injury patterns, systemic inflammatory response, and impairment of various organ functions, reflects characteristics of human AT. In the future, this model may help to study the complex immuno-pathophysiological consequences and innovative therapeutic approaches after blunt AT.

First European Haplotype of Echinococcus multilocularis Identified in the United States: An Emerging Disease?

BACKGROUND: Echinococcus multilocularis is one of the most severe and lethal parasitic diseases of humans, most often reported in Europe and Asia. Only 1 previous case has been documented in the contiguous United States from Minnesota in 1977. European haplotypes have been identified in carnivores and domestic dogs as well as recently in patients in western and central Canada. METHODS: We used immunohistochemical testing with the monoclonal antibody Em2G11 and a species-specific enzyme-linked immunosorbent assay affinity-purified antigen Em2, as well as COX1 gene sequencing. RESULTS: Using pathology, immunohistochemical staining, specific immunodiagnostic testing, and COX1 gene sequencing, we were able to definitively identify E. multilocularis as the causative agent of our patient's liver and lung lesions, which clustered most closely with the European haplotype. CONCLUSIONS: We have identified the first case of a European haplotype E. multilocularis in the United States and the first case of this parasitic infection east of the Mississippi River. Given the identification of this haplotype in Canada, this appears to be an emerging infectious disease in North America.

Successful hematopoietic stem cell transplantation in a 4-1BB deficient patient with EBV-induced lymphoproliferation.

Complete remission from recurrent EBV-positive lymphoma is not mandatory before HSCT to achieve long-term cure in a patient suffering from a recently described immunodeficiency affecting the T-cell coactivation molecule 4-1BB.

Genome-wide DNA methylation analysis along the progression of gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type.

Extra-nodal marginal zone B-cell lymphoma (MZBL) of mucosa-associated lymphoid tissue is an indolent lymphoma mostly affecting the gastrointestinal tract. The lymphoma initially has small-cell morphology (SC-MZBL) and often arises in the background of Helicobacter pylori-induced gastritis. In some cases, a clonal malignant progression to large-cell morphology (LC-MZBL) is observed. Here, we studied the DNA methylation profile of 30 gastric MZBLs along their progression. Genome-wide DNA methylation profiling, identified 7698 significantly differentially methylated loci during gastric MZBL progression (σ/σmax ≥0·4, q ≤ 0·001). LC-MZBL showed hypermethylation in comparison to SC-MZBL with an enrichment of regions involved in transcriptional regulation. In conclusion, our present data show that the morphological distinction between SC- and LC-MZBL is reflected by characteristic DNA methylation profiles.

H3F3A-mutated giant cell tumour of bone without giant cells-clinical presentation, radiology and histology of three cases.

AIMS: Giant cell tumour of bone (GCTB) is histologically defined as a lesion containing reactive giant cells and a neoplastic mononuclear cell population; in up to 92% of cases, GCTB is characterised by a specific mutation of the histone gene H3F3A. The cellular composition ranges from giant-cell-rich to giant-cell-poor. The diagnosis of GCTB can be challenging, and several other lesions need to be excluded, e.g. aneurysmal bone cysts, non-ossifying fibromas, chondroblastomas, brown tumours, and giant-cell-rich osteosarcomas. Our aim was to analyse the clinical history, imaging, molecular pathology and histology of three H3F3A-mutated bone tumours without detectable giant cells. None of the patients received denosumab therapy. METHODS AND RESULTS: Diagnostic material was obtained by curettage or resection and/or biopsy. Common histomorphological features of all three reported lesions were fibrocytic, oval cells in a background of osteoid and an absence of multinuclear giant cells as confirmed with CD68 immunohistochemistry. We used immunohistochemistry and Sanger sequencing to demonstrate positivity for the H3.3 p.G34W mutation. Differential diagnoses were systematically excluded on the basis of histomorphology, immunohistochemistry, and fluorescence in-situ hybridisation. The imaging (radiography, computed tomography, and magnetic resonance imaging) for all three cases is presented and discussed. CONCLUSIONS: We believe that these GCTBs without giant cells expand one end of the heterogeneous range of GCTB. Because of the lack of giant cells, correct diagnosis of GCTB is challenging or even impossible on histological grounds alone. In these cases, detection of the characteristic H3F3A mutation (G34W-specific antibody RM263 or sequencing) is extremely helpful for diagnosing those lesions without giant cells as giant cell tumours of bone.

A phase II study of the PI3K inhibitor copanlisib in combination with the anti-CD20 monoclonal antibody rituximab for patients with marginal zone lymphoma: treatment rationale and protocol design of the COUP-1 trial.

BACKGROUND: Advanced stage marginal zone lymphoma (MZL) is an incurable indolent B-cell lymphoma, for which a wide variety of treatments ranging from single agent rituximab to more dose intense immunochemotherapy exists. One of the major goals in this palliative setting is to develop chemotherapy-free treatments, which approach the efficacy of immunochemotherapies, but avoid chemotherapy associated toxicity in this often elderly patient population. The PI3K inhibitor copanlisib has recently shown remarkable clinical activity in refractory or relapsed indolent B-cell lymphomas, among them MZL. Based on these data, copanlisib monotherapy was granted breakthrough designation by the FDA for the treatment of adult patients with relapsed marginal zone lymphoma who have received at least two prior therapies. However, data are still limited in particular for MZL. Based on this, the COUP-1 trial aims at testing the toxicity and efficacy of copanlisib in combination with rituximab in treatment naive and relapsed MZL. METHODS: COUP-1 is a prospective, multicenter, single-arm, open-label, non-randomized phase II trial of 6 cycles (28 days cycle) of copanlisib (60 mg intravenous day 1, 8, 15) and rituximab (375 mg/m2 intravenous day 1) in the induction phase followed by a maintenance phase of copanlisib (d1, d15 every 4 weeks for a maximum of 12 cycles) and rituximab (d1 every 8 weeks for a maximum of 12 cycles) in patients aged ≥18 years with previously untreated or relapsed MZL in need of treatment. A total of 56 patients are to be enrolled. Primary endpoint is the complete response (CR) rate determined 12 months after start of induction therapy. Secondary endpoints include the overall response (OR) rate, progression free survival (PFS), overall survival (OS), safety and patient related outcome with quality of life. The study includes a translational bio-sampling program with the prospect to measure minimal residual disease. The study was initiated in November 2019. DISCUSSION: The COUP-1 trial evaluates the efficacy and toxicity of the treatment of copanlisib in combination with rituximab in patients with MZL and additionally offers the chance for translational research in this heterogenous type of lymphoma. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03474744 . Registration date: 03/23/2018.

Foveal configurations with disappearance of the foveal pit in eyes with macular pucker: Presumed role of Müller cells in the formation of foveal herniation.

Many eyes with macular pucker are characterized by a centripetal displacement of the inner foveal layers which may result in a disappearance of the foveal pit. In this retrospective case series of 90 eyes with macular pucker of 90 patients, we describe using spectral-domain optical coherence tomography different foveal configurations with ectopic inner foveal layers, document the relationship between posterior vitreous detachment (PVD) and idiopathic epiretinal membrane (ERM) formation and spontaneous and postoperative morphological alterations of the fovea, and propose an active role of Müller cells in the development of foveal herniation. We found that ERM were formed during or after partial perifoveal PVD, or after foveal deformations caused by tissue edema. The ERM-mediated centripetal displacement of the inner foveal layers and in various eyes anterior hyaloidal traction caused a disappearance of the foveal pit and an anterior stretching of the foveola with a thickening of the central outer nuclear layer (ONL). After the edges of the thickened inner layers of the foveal walls moved together, continuous centripetal displacement of the inner foveal layers generated a bulge of the fovea towards the vitreous (foveal herniation). Macular pseudoholes with a herniation of the inner foveal layers show that the outer layer of the protruding foveal walls is the outer plexiform layer (OPL). If the ERM covered the foveal walls and parafova, but not the foveola, the inner layers of the foveal walls were not fully centripetally displaced and the foveal pit was present. The visual acuity of eyes with ectopic inner foveal layers was inversely correlated with the thickness of the foveal center. Spontaneous morphological alterations after disappearance of the foveal pit may include the development of cystoid macular edema or additional thickening of the foveal tissue and foveal herniation. The foveal configuration with ectopic inner layers of the foveal walls and a thick central ONL persisted over longer postoperative time periods. The data show that the centripetal displacement of the inner foveal layers in eyes with macular pucker, which results in a disappearance of the foveal pit, may also generate foveal herniation which is suggested to be caused by contraction of Müller cell processes in the OPL. The centripetal displacement of the inner foveal layers and the formation of foveal herniation are suggested to reverse the foveal pit formation during development.

Different modes of full-thickness macular hole formation.

Full-thickness macular holes (FTMH) are an important cause of visual deterioration. However, different modes of FTMH formation are less investigated. It is also not clear whether the development of edematous cysts contributes to FTMH formation. In this retrospective case series of 30 eyes of 30 patients, we describe using spectral-domain optical coherence tomography different modes of FTMH formation. Morphological alterations of established FTMH are shown in 5 eyes of 5 patients. We found in 2 of 30 eyes investigated that anterior hyaloidal traction induced a hyperreflectivity of the inner Müller cell layer of the foveola prior to FTMH formation. In 3 eyes, FTMH were caused by anterior hyaloidal traction which produced foveal pseudocysts that developed to an outer lamellar hole (OLH) characterized by a disruption of the central outer retina. The OLH developed to a FTMH by the disruption of the inner layer of the foveola. FTMH formation from an OLH by hyaloidal traction was observed also in further 7 eyes. In 2 eyes, the OLH, which preceded FTMH formation, was generated by a serous retinal detachment. In 3 eyes, anterior hyaloidal traction caused a detachment of the fovea from the retinal pigment epithelium (RPE); the subsequent disruption of the foveola resulted in a FTMH. Six eyes showed the development of a FTMH from a degenerative lamellar hole (DLH). In 5 eyes with macular pucker, FTMH were formed by traction of epiretinal membranes (ERM) or hyaloidal traction. Two eyes showed the development of a FTMH by anterior or tangential hyaloidal traction likely without a formation of an OLH. FTMH formation from an OLH proceeded with or without an enlargement of cystic cavities in the foveal walls. The formation of FTMH from a DLH, after a detachment of the fovea, and in macular pucker eyes was associated with a formation of cystic cavities in the foveal walls. The best-corrected visual acuity (BCVA) of eyes with an OLH or FTMH was inversely correlated to the base and minimum diameters of the holes, and with the height of the foveal walls; the highest correlation coefficients were found between the BCVA and the base diameter. The data show that FTMH may be formed via different modes by hyaloidal traction and/or traction of ERM, or after a serous retinal detachment. It is suggested that, after FTMH formation, the impaired fluid clearance through the RPE after detachment of the central outer retina causes the development of edematous cysts in the foveal walls which enlarges the FTMH. The BCVA of eyes with an OLH or FTMH mainly depends on the size of the central photoreceptor-free area.

Case Report and Review of the Literature of a Rare Entity of a Uterine Fibroid: A Genital Rhabdomyoma.

Extracardiac rhabdomyomas are rare benign tumors. According to histopathologic and clinical characteristics, they are divided into 3 subgroups: adult, fetal, and genital rhabdomyomas. Various adult extracardiac rhabdomyomas have been reported in the head and neck region, whereas genital rhabdomyomas are uncommon. Here, we report on a uterine genital rhabdomyoma in a 32-yr-old woman with secondary sterility. After myomectomy, the histopathologic analysis showed a slow cycling tumor with striated muscle differentiation and without any evidence of malignancy. Immunohistochemical staining proved coexpression of actin, caldesmon, and desmin. To the best of our knowledge, this is the first case of a uterine-based genital rhabdomyoma.

Emerging human alveolar echinococcosis in Hungary (2003-2018): a retrospective case series analysis from a multi-centre study.

BACKGROUND: Human alveolar echinococcosis (AE) caused by Echinococcus multilocularis is an underreported, often misdiagnosed and mistreated parasitic disease mainly due to its low incidence. The aim of this study was to describe the epidemiological and clinical characteristics of human AE patients in Hungary for the first time. METHOD: Between 2003 and 2018, epidemiological and clinical data of suspected AE patients were collected retrospectively from health database management systems. RESULTS: This case series included a total of 16 AE patients. The mean age of patients was 53 years (range: 24-78 years). The sex ratio was 1:1. Four patients (25%) revealed no recurrence after radical surgery and adjuvant albendazole (ABZ) therapy. For five patients (31.3%) with unresectable lesions, a stabilization of lesions with ABZ treatment was achieved. In seven patients (43.8%), progression of AE was documented. The mean diagnostic delay was 33 months (range: 1-122 months). Three AE related deaths (fatality rate 18.8%) were recorded. CONCLUSIONS: AE is an emerging infectious disease in Hungary with a high fatality rate since based on our results, almost every fifth AE patient died in the study period. Differential diagnosis and appropriate surgical and medical therapy for AE is an urging challenge for clinicians in Hungary, as well as in some other European countries where E. multilocularis is prevalent.

Analysis of vascularization in thyroid gland nodes with superb microvascular imaging (SMI) and CD34 expression histology: a pilot study.

BACKGROUND: The Doppler sonography technique known as "superb microvascular imaging" (SMI) is advancing sonographic micro vascularization imaging in various disciplines. In this study, we aimed to determine whether SMI could reliably reproduce the blood flow in thyroid nodes and whether malignancy could be diagnosed, based on vascularization properties. Immunhistochemical staining by CD34 and SMI where used to determine the vascularization of nodes in terms of quantified vascularization parameters gained by computational evaluation. METHODS: We used image analysis programs to investigate whether the quantitative value for vascularization strength in the thyroid node, measured with SMI, was correlated with the actual degree of vascularization, determined microscopically. We included 16 patients that underwent thyroid resections. We prepared thyroid gland tissue slices for immunohistochemistry and labelled endothelial cells with CD34 to visualize blood vessels microscopically. We used image analysis programs, ImageJ, to quantify SMI Doppler sonographic measurements and CellProfiler to quantify CD34 expression in histological sections. We evaluated the numeric values for diagnostic value in node differentiation. Furthermore, we compared these values to check for correlations. RESULTS: Among the 16 nodes studied, three harboured malignant tumours (18.75%): two papillary and one follicular carcinoma. Among the 13 benign lesions (81.25%), four harboured follicular adenomas. Malignant and benign nodes were not significantly different in sonographic (0.88 ± 0.89 vs. 1.13 ± 0.19; p = 0.2790) or immunohistochemical measurements of vascularization strength (0.05 ± 0.05 vs. 0.08 ± 0.06; p = 0.2260). CONCLUSION: We found a positive, significant correlation (r = 0.55588; p = 0.0254) between SMI (quantitative values for vascularization strength) and immunohistochemistry (CD34 staining) evaluations of thyroid nodes.

Degenerative lamellar macular holes: tractional development and morphological alterations.

PURPOSE: The development of degenerative lamellar macular holes (DLH) is largely unclear. This study was aimed at documenting with spectral-domain optical coherence tomography the tractional development and morphological alterations of DLH. METHODS: A retrospective case series of 44 eyes of 44 patients is described. RESULTS: The development of DLH is preceded for months or years by tractional deformations of the fovea due to the action of contractile epiretinal membranes (ERM) and/or the partially detached posterior hyaloid, or by cystoid macular edema (CME). DLH may develop after a tractional stretching and thickening of the foveal center, from a foveal pseudocyst, after a detachment of the foveola from the retinal pigment epithelium, a disruption of the foveal structure due to CME, and after surgical treatment of tractional lamellar or full-thickness macular holes (FTMH). The foveal configuration of a DLH can be spontaneously reestablished after short transient episodes of CME and a small FTMH. A DLH can evolve to a FTMH by traction of an ERM. Surgical treatment of a DLH may result in an irregular regeneration of the foveal center without photoreceptors. CONCLUSIONS: Tractional forces play an important role in the development of DLH and in the further evolution to FTMH. It is suggested that a DLH is the result of a retinal wound repair process after a tractional disruption of the Müller cell cone and a degeneration of Henle fibers, to prevent a further increase in the degenerative cavitations.

Phase II trial evaluating the efficacy and safety of the anti-CD20 monoclonal antibody obinutuzumab in patients with marginal zone lymphoma.

Marginal zone lymphoma (MZL) belongs to the group of indolent B-cell non-Hodgkin's lymphomas, which is characterized by an indolent course. In this mostly elderly patient population, the development of chemotherapy-free approaches is of particular interest. In this situation, single-agent treatment with the next-generation anti-CD20 antibody obinutuzumab is an attractive approach, which promises high efficacy without major toxicity. We describe here an open-label, multicentric Phase II trial evaluating the efficacy and safety of obinutuzumab in de novo MZL patients, who are treatment naive for systemic therapy and not eligible for or failed local treatment. ClinicalTrials.gov identifier NCT03322865.

[The gut: center of immunity : Rare inflammatory bowel diseases caused by immunodeficiencies]. / Der Darm im Fokus des Immunsystems : Seltene Darmerkrankungen bei primären Immundefekten.

The gut is the largest immune organ of the human body with an enormous mucosal interface. By acting as a physical barrier and by hosting many of the body's immune cells and tissues, the gut is the first line of defense against potentially harmful substances. Therefore, diseases leading to impaired immune response or disruption of the epithelial barrier result in autoimmune, infectious, or inflammatory bowel disease, frequently associated with diarrhea, malabsorption, melena, and growth failure. The differential diagnosis represents an interdisciplinary challenge in this group of rare diseases. The diseases are characterized by clinical, immunological, and histopathological features caused by mutations in single genes. In the following, we will focus on histological findings within the various entities of immunodeficiencies.