The embryo-placental CD15-positive "vasculogenic zones" as a source of propranolol-sensitive pediatric vascular tumors.

Abstract Objective Propranolol-induced involution is a unique biological feature of some pediatric vascular tumors, for instance infantile hemangioma (IH), cerebral cavernoma or chorioangioma. Currently, the cellular origin of these distinct tumors is unclear. In this study, we tested the hypothesis that propranolol-responsive vascular tumors are derived from common vessel-forming CD15 + progenitor cells which occur in early gestation. The aim of this study was to identify the tumor-relevant CD15 + progenitors at the early stages of embryo-placental development. Materials and methods Human embryo-placental units of 4–8 weeks gestation and pediatric vascular tumors were tested for expression…

Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma

Simple Summary Individual patients with liver cancer have a highly variable clinical course. Hence, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Expression of two key enzymes in pyrimidine synthesis was analyzed in a large, well-characterized cohort of patients with liver cancer. Dysregulated expression of these enzymes was associated with shorter survival of the patients. A combined score of both markers was found to be a statistically independent prognostic marker. Abstract Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic mar…

TGFβ-activated kinase 1 (TAK1) is activated and predicts prognosis in hepatocellular carcinoma

13P Comparison study of different programmed death-ligand 1 (PD-L1) assays, readers and scoring methods in triple-negative breast cancer (TNBC)

Mismatch Reparatur Defizienz, Chemotherapie und Überleben bei resektablem Magenkarzinom: Eine Beobachtungsstudie der deutschen Zentren des staR-Projekts und eine Metaanalyse

Role of Hypoxia and the Adenosine System in Immune Evasion and Prognosis of Patients with Brain Metastases of Melanoma: A Multiplex Whole Slide Immunofluorescence Study

Simple Summary The introduction of immune-checkpoint inhibitors improved the therapeutic landscape for patients with advanced malignant melanoma. However, many patients, including patients with melanoma brain metastases, do not derive benefit from immune-checkpoint blockade. Hence, biomarkers are needed to identify potential mechanisms of resistance and optimize patient selection. This study aimed to explore the role of hypoxia-mediated immunosuppression within the tumor microenvironment of patients with metastatic melanoma using multiplex immunofluorescence. We analyzed the prognostic relevance of the hypoxia surrogate marker GLUT-1, the adenosine-synthesizing ectoenzymes CD73/CD39, and th…

Dissatisfaction with post-operative pain management—A prospective analysis of 1071 patients

Summary A total number of 1071 patients was investigated using a modified questionnaire of the American Pain Society to evaluate the pain profile and satisfaction/dissatisfaction on the second post-operative day after different types of surgery (abdominal, traumatic, orthopaedic, urologic, gynaecologic, ENT). Patients were either treated with non-standardized pain management (no measurement of pain intensities, no regular administration of analgesics) (non-APS; n = 575) under responsibility of surgical specialties or with standardized pain management (regular assessment of pain and dose adaptation with i.v. PCA or epidurals) (APS; n = 496) by an anaesthesiology-based acute pain service. Pat…

Reproducibility and concordance of 4 clinically developed programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays in triple-negative breast cancer (TNBC)

Abstract Background Atezolizumab (an anti–PD-L1 antibody) has shown clinical activity alone or in combination with nab-paclitaxel in patients (pts) with first-line metastatic TNBC who have PD-L1 expression on their tumour-infiltrating immune cells (IC). We analysed the performance of 4 PD-L1 IHC assays for PD-L1 IC expression in TNBC. Methods Thirty archival TNBC tissue specimens were selected from a set of 107 based on PD-L1 IC expression per VENTANA SP142 ( 5%: 8 cases), to represent the distribution of PD-L1 IC–positivity in the pivotal atezolizumab studies (Emens et al., SABCS 2018; JAMA Oncol 2019). Serial histologic sections were stained with VENTANA SP142 and SP263, and DAKO 22C3 and…

A multicentre analytical comparison study of inter-reader and inter-assay agreement of four programmed death-ligand 1 immunohistochemistry assays for scoring in triple-negative breast cancer.

AIMS Studies in various cancer types have demonstrated discordance between results from different programmed death-ligand 1 (PD-L1) assays. Here, we compare the reproducibility and analytical concordance of four clinically developed assays for assessing PD-L1-positivity in tumour-infiltrating immune cells in the tumour area (PD-L1-IC-positivity) in triple-negative breast cancer (TNBC). METHODS AND RESULTS Primary TNBC resection specimens (n = 30) were selected based on their PD-L1-IC-positivity per VENTANA SP142 ( 5%: eight cases). Serial histological sections were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3 and DAKO 28-8. PD-L1-IC-positivity and tumour cell expression (…

Multimodal Deep Learning for Prognosis Prediction in Renal Cancer

BackgroundClear-cell renal cell carcinoma (ccRCC) is common and associated with substantial mortality. TNM stage and histopathological grading have been the sole determinants of a patient’s prognosis for decades and there are few prognostic biomarkers used in clinical routine. Management of ccRCC involves multiple disciplines such as urology, radiology, oncology, and pathology and each of these specialties generates highly complex medical data. Here, artificial intelligence (AI) could prove extremely powerful to extract meaningful information to benefit patients.ObjectiveIn the study, we developed and evaluated a multimodal deep learning model (MMDLM) for prognosis prediction in ccRCC.Desig…

<i>BRAF</i> Mutation Testing in Lynch Syndrome Diagnostics: Performance and Efficiency According to Patient's Age

Background: BRAF V600E mutations are reportedly associated with sporadic microsatellite-unstable (MSI) colorectal cancer (CRC), while rarely detected in CRCs of Lynch syndrome (LS) patients. Therefore, current international diagnostic guidelines recommend somatic BRAF mutation testing in MLH1-deficient MSI CRC patients to exclude LS. As sporadic BRAF- mutant MSI CRC is a disease of the elderly, while LS-associated CRC usually occurs at younger age, we hypothesized that the efficacy of BRAF testing in LS diagnostics may be age-dependent. Methods: We systematically compared the prevalence of BRAF mutations in LS-associated CRCs and MSI CRCs from population-based cohorts in different age group…

Knockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Faslpr Mice

KH-type splicing regulatory protein (KSRP) is an RNA-binding protein that promotes mRNA decay and thereby negatively regulates cytokine expression at the post-transcriptional level. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated cytokine expression causing multiple organ manifestations

Colonoscopy and reduction of colorectal cancer risk by molecular tumor subtypes: a population-based case-control study

AbstractObjectiveIn previous studies, the protective effect of colonoscopy was generally stronger for distal than for proximal colorectal cancer (CRC). This study aimed to investigate whether the association of colonoscopy and CRC risk varies according to major molecular pathological features and pathways of CRC.DesignPopulation-based case-control study from Germany, including 2132 patients with a first diagnosis of CRC and information on major molecular tumor markers, and 2486 control participants without CRC. Detailed participant characteristics were collected by standardized questionnaires and information on previous colonoscopy was derived from medical records. Polytomous logistic regre…

Reproducibility and concordance of 4 clinically developed programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays in triple negative breast cancer (TNBC)

Abstract Background Atezolizumab (an anti–PD-L1 antibody) has shown clinical activity alone or in combination with nab-paclitaxel in patients (pts) with first-line metastatic TNBC who have PD-L1 expression on their tumour-infiltrating immune cells (IC). We analysed the performance of 4 PD-L1 IHC assays for PD-L1 IC expression in TNBC. Methods Thirty archival TNBC tissue specimens were selected from a set of 107 based on PD-L1 IC expression per VENTANA SP142 ( 5%: 8 cases), to represent the distribution of PD-L1 IC–positivity in the pivotal atezolizumab studies (Emens et al., SABCS 2018; JAMA Oncol 2019). Serial histologic sections were stained with VENTANA SP142 and SP263, and DAKO 22C3 and…

Renal tubular epithelial cell-derived BAFF expression mediates kidney damage and correlates with activity of proliferative lupus nephritis in mouse and men.

B-cell activating factor of the tumour necrosis factor family (BAFF) is a cytokine, mainly produced by hematopoietic cells (e.g. monocytes/macrophages, dendritic cells), indispensable for B-cell maturation. The BLISS studies have demonstrated that blocking BAFF by the human monoclonal antibody belimumab is a valuable therapeutic approach in patients with clinically and serologically active systemic lupus erythematosus (SLE). However, the defined sources of BAFF, which contributes to SLE, are still unclear. Recent findings show that BAFF expression is not restricted to myeloid cells. Since lupus nephritis is the main cause of morbidity and mortality for SLE patients, the aim of this study wa…

Deep learning for diagnosis and survival prediction in soft tissue sarcoma.

Background Clinical management of soft tissue sarcoma (STS) is particularly challenging. Here, we used digital pathology and deep learning (DL) for diagnosis and prognosis prediction of STS. Patients and methods Our retrospective, multicenter study included a total of 506 histopathological slides from 291 patients with STS. The Cancer Genome Atlas cohort (240 patients) served as training and validation set. A second, multicenter cohort (51 patients) served as an additional test set. The use of the DL model (DLM) as a clinical decision support system was evaluated by nine pathologists with different levels of expertise. For prognosis prediction, 139 slides from 85 patients with leiomyosarcom…

HILPDA is upregulated, predicts prognosis and promotes cancer progression in hepatocellular carcinoma

ANKRD26-RET - A novel gene fusion involving RET in papillary thyroid carcinoma

Abstract Background Rearrangements of RET are drivers of oncogenesis, traceable in different cancer types as papillary thyroid carcinoma (PTC), non-small cell lung cancer, colorectal or breast cancer. Anchored multiplex PCR based next-generation sequencing (NGS) can detect RET rearrangements involving previously unknown partner genes. Methods A sample of PTC underwent NGS, following detection of RET rearrangement by fluorescence in situ hybridization. Expression analysis of ANKRD26 and RET was performed for the tumor harboring ANKRD26-RET, for corresponding normal thyroid tissue and PTC tumors with representative genetic alterations (BRAFV600E, CCDC6-RET), complemented by a comparative sear…

Deep Learning Predicts Molecular Subtype of Muscle-invasive Bladder Cancer from Conventional Histopathological Slides.

Abstract Background Muscle-invasive bladder cancer (MIBC) is the second most common genitourinary malignancy, and is associated with high morbidity and mortality. Recently, molecular subtypes of MIBC have been identified, which have important clinical implications. Objective In the current study, we tried to predict the molecular subtype of MIBC samples from conventional histomorphology alone using deep learning. Design, setting, and participants Two cohorts of patients with MIBC were used: (1) The Cancer Genome Atlas Urothelial Bladder Carcinoma dataset including 407 patients and (2) our own cohort including 16 patients with treatment-naive, primary resected MIBC. This resulted in a total …

Novel rearrangements involving the RET gene in papillary thyroid carcinoma.

Abstract Background In the field of gene fusions driving tumorigenesis in papillary thyroid carcinoma (PTC), rearrangement of the proto-oncogene RET is the most frequent alteration. Apart from the most common rearrangement of RET to CCDC6, more than 15 partner genes are yet reported. The landscape of RET rearrangements in PTC (“RET-PTC”) can notably be enlarged by modern targeted next-generation sequencing, indicating similarities between oncogenic pathways in other cancer types with identical genetic alterations. Methods Targeted next-generation sequencing was performed for two cases of BRAF-wild type PTC with confirmation of the results by Sanger sequencing. A “UniProt” database research …

Interassay and interobserver comparability study of four programmed death-ligand 1 (PD-L1) immunohistochemistry assays in triple-negative breast cancer

Different immunohistochemical programmed death-ligand 1 (PD-L1) assays and scorings have been reported to yield variable results in triple-negative breast cancer (TNBC). We compared the analytical concordance and reproducibility of four clinically relevant PD-L1 assays assessing immune cell (IC) score, tumor proportion score (TPS), and combined positive score (CPS) in TNBC. Primary TNBC resection specimens (n = 104) were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3, and DAKO 28–8. PD-L1 expression was scored according to guidelines on virtual whole slide images by four trained readers. The mean PD-L1 positivity at IC-score ≥1% and CPS ≥1 ranged between 53% and 75% with th…

The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration

The high-mobility group box 1 (HMGB1) protein has a central role in immunological antitumour defense. Here we show that natural killer cell-derived HMGB1 directly eliminates cancer cells by triggering metabolic cell death. HMGB1 allosterically inhibits the tetrameric pyruvate kinase isoform M2, thus blocking glucose-driven aerobic respiration. This results in a rapid metabolic shift forcing cells to rely solely on glycolysis for the maintenance of energy production. Cancer cells can acquire resistance to HMGB1 by increasing glycolysis using the dimeric form of PKM2, and employing glutaminolysis. Consistently, we observe an increase in the expression of a key enzyme of glutaminolysis, malic …

DNA methylation profiling to explore colorectal tumor differences according to menopausal hormone therapy use in women

Aim: Use of menopausal hormone therapy (MHT) has been associated with a reduced risk for colorectal cancer, but mechanisms underlying this relationship are not well understood. In the colon, MHT appears to act through estrogen receptor β (ERβ) which may influence DNA methylation by binding to DNA. Using genome-wide methylation profiling data, we aimed to identify genes that may be differentially methylated according to MHT use. Materials & methods: DNA methylation was measured using Illumina HumanMethylation450k arrays in two independent tumor sample sets of colorectal cancer patients. Differential methylation was determined using R/limma. Results: In the discovery analysis, two CpG si…

Pulmonary microvascular architecture in hereditary haemorrhagic telangiectasia

A 24-year-old Caucasian man was admitted with a known hereditary haemorrhagic telangiectasia (HHT) and heterozygous mutation of factor V Leiden following episodes of cerebral infarctions in occipital lobes, cerebellum and brainstem. In his case history, the patient underwent several interventional embolisation of arteriovenous (AV) malformations in the middle and lower lobes (figure 1). However, those were not completely successful as the malformations were diffuse. We performed video-assisted thoracoscopic surgery with a resection of the middle lobe and a wedge resection of segment 10. Figure 1 CT scans depict the pulmonary arteriovenous malformations after re-embolisation in the middle lo…

Mehrwert von EUS gesteuerten Fein-Nadel-Biopsien (FNB) gegenüber FN-Aspiration (FNA) von unklaren Läsionen im Gastrointestinal (GI)-Trakt

Genome-wide DNA methylation differences according to oestrogen receptor beta status in colorectal cancer.

Involvement of sex hormones in colorectal cancer (CRC) development has been linked to oestrogen receptor β (ERβ). Expression of ERβ is found reduced in tumour tissue and inversely related to mortality. However, mechanisms are not well understood. Our study aimed to detect differentially methylated genes associated with ERβ expression, which could point to mechanisms by which ERβ could influence risk and prognosis of CRC. Epigenome-wide DNA methylation profiling was performed using Illumina HumanMethylation450k BeadChip arrays in two independent tumour sample sets of CRC patients recruited in 2003–2010 by the German DACHS study (discovery cohort n = 917, replication cohort n = 907). ERβ expr…

Lipid droplets and associated proteins in viral hepatitis

317 Role of integrins in the metastatic spread of high-grade serous ovarian cancer

Introduction/Background* In high-grade serous ovarian cancer (HGSOC) an early intraperitoneal metastatic spread is common which determines the therapeutical approach and prognosis. Integrins may be involved in metastatic spread of HGSOC. In this study, integrin expression was examined in primary tumour and metastases of HGSOC. Methodology The expression of integrin α2, α4, α5, α6, and β1 was assessed by immunostaining in tumour samples of the ovary, omentum, and peritoneum of each patient. Differences in integrin expression among tumour localisations and their association with clinicopathological parameters were examined by Fisher’s exact test. The impact of integrin expression on progressi…

Application of Patient-Derived Liver Cancer Cells in Personalized Treatment Approach: Phenotypic Characterization and Therapeutic Target Identification

Clinicopathological Significance of Syndecan-1 in Cholangiocarcinoma: A Study Based on Immunohistochemistry and Public Sequencing Data

Background: Syndecan-1 (CD138

A phase II, open label, multicenter trial of avelumab in patients with advanced, metastatic high-grade neuroendocrine carcinomas NEC G3 (WHO 2010) progressive after first-line chemotherapy (AVENEC).

4103 Background: High grade Neuroendocrine Neoplasias (NEN) are rare tumors with a poor prognosis and no established second line therapy when progressive after first line platinum-based chemotherapy resulting in a median overall survival (OS) of 5 months. This study aims to evaluate the efficacy and safety of the anti-programmed death ligand-1 (PD-L1) antibody Avelumab in patients (pts) with NEN G3 progressing after first-line chemotherapy. Methods: In a multicenter, national, single-arm, open-label, phase II trial the efficacy and safety of Avelumab was evaluated in patients with metastatic progressive Neuroendocrine Carcinomas (NEC G3) according to WHO 2010, excluding Merkel cell carcino…

Dolichomegaösophagus bei Achalasie

HISTORY AND CLINICAL FINDINGS A 78-year-old woman suffered from achalasia since 63 years with a progressive decompensation over the last year. 53 years ago, treatment with the Stark Dilator and 24 years ago, pneumatic dilation had been carried out. Currently, the patient presented with dysphagia for liquid and solid food, with permanent retrosternal pain and regurgitation for every meal, leading to a weight loss of 10 kg. INVESTIGATIONS The barium esophagogram showed a marked dilation of the esophagus with retinated secretions and food. The cardia had a maximum width of 15 mm. On endoscopy, reflux esophagitis and an insufficient lower esophageal sphincter were evident. TREATMENT AND COURSE …

PD-L1 Expression and Immune Cell Infiltration in Gastroenteropancreatic (GEP) and Non-GEP Neuroendocrine Neoplasms With High Proliferative Activity

The potential of neuroendocrine neoplasms (NEN) to respond to checkpoint inhibitors is largely unknown and full of great expectations. Immunohistochemical (IHC) studies of programmed cell death ligand 1 (PD-L1) expression in the tumor microenvironment and its implications in predicting the response to checkpoint inhibition is a very active subject. Currently, the combined analysis of PD-L1 expression and tumor-associated immune cell (TAIC) infiltration is considered the best predictive marker of therapeutic response. Here we investigated the expression of PD-L1 on tumor cells (TC) and tumor-infiltrating immune cells (IC) by IHC in 68 NEN samples with a high proliferation rate (Ki-67 >20%…

Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification.

Primary liver cancer (PLC) ranks among the most lethal solid cancers worldwide due to lack of effective biomarkers for early detection and limited treatment options in advanced stages. Development of primary culture models that closely recapitulate phenotypic and molecular diversities of PLC is urgently needed to improve the patient outcome. Long-term cultures of 7 primary liver cancer cell lines of hepatocellular and cholangiocellular origin were established using defined culture conditions. Morphological and histological characteristics of obtained cell lines and xenograft tumors were analyzed and compared to original tumors. Time course analyses of transcriptomic and genomic changes were…

Immaturity for gestational age of microvasculature and placental barrier in term placentas with high weight

Abstract Objective Villous immaturity for gestational age is a multifactorial developmental deviation associated with unexpected placental insufficiency, fetal hypoxia and term fetal death. In our previous work we have shown that immature CD15+/CD31+/CD34+ endothelial cells were an important indicator of placental villous immaturity and chronic insufficiency. The aim of this study was to perform a comparative analysis of CD15-marked immaturity in the vessel walls between normal and pathological term placentas of clinically and structurally heterogenous groups with normal, low and high weight. Study design 165 clinically normal and pathological placentas of gestational age 39–42 with normal …

Distinct Activities of Glycolytic Enzymes Identify Chronic Lymphocytic Leukemia Patients with a more Aggressive Course and Resistance to Chemo-Immunotherapy.

A higher capacity to grow under hypoxic conditions can lead to a more aggressive behavior of tumor cells. Determining tumor activity under hypoxia may identify chronic lymphocytic leukemia (CLL) with aggressive clinical course and predict response to chemo-immunotherapy (CIT). A metabolic score was generated by determining pyruvate kinase and lactate dehydrogenase, key enzymes of glycolysis, ex vivo in primary CLL samples under normoxic and hypoxic conditions. This score was further correlated with clinical endpoints and response to CIT in 96 CLL patients. 45 patients were classified as metabolic high risk (HR), 51 as low risk (LR). Treatment-free survival (TFS) was significantly shorter in…

Particles of vaterite, a metastable CaCO3polymorph, exhibit high biocompatibility for human osteoblasts and endothelial cells and may serve as a biomaterial for rapid bone regeneration

We have previously described a promising alternative to conventional synthetic bone biomaterials using vaterite, a metastable CaCO3 polymorph that increases the local Ca2+ concentration in vitro and leads to an oversaturation of phosphate, the primary bone mineral. This stimulates a natural bone-like mineralisation in a short period of time. In this study, sterile and endotoxin-free vaterite particles were synthesised in a nearly quantitative yield. The 500-1,000 nm vaterite particles did not exhibit any cytotoxic effects as measured by MTS, lactate dehydrogenase, or crystal violet assays on the human osteoblast cell line (MG-63) exposed to concentrations up to 500 μg/ml vaterite up to 72 h…

High TCTP expression as prognostic factor in different cancer types

CD15 immunostaining improves placental diagnosis of fetal hypoxia

Fetal hypoxic events with unclear predictive value are a common indication for placenta examination. We evaluated whether the use of CD15 immunostaining can improve the assessment of severity and duration of fetal hypoxia.We compared placentas (37-42 gestational weeks) from stillborns/newborns with birth asphyxia (BA) and non-hypoxic newborns. Placental findings were studied in following groups: (1) acute BA (n = 11) due to placental abruption, (2) non-acute BA (n = 121) due to non-acute conditions, (3) non-BA (n = 46) in pregnancies with preeclampsia and gestational diabetes, and (4) controls (n = 30).A high expression of CD15 in feto-placental resistance vessels (FRVs) was present in non-…

Genome-wide DNA methylation differences according to oestrogen receptor beta status in colorectal cancer

Involvement of sex hormones in colorectal cancer (CRC) development has been linked to oestrogen receptor β (ERβ). Expression of ERβ is found reduced in tumour tissue and inversely related to mortality. However, mechanisms are not well understood. Our study aimed to detect differentially methylated genes associated with ERβ expression, which could point to mechanisms by which ERβ could influence risk and prognosis of CRC. Epigenome-wide DNA methylation profiling was performed using Illumina HumanMethylation450k BeadChip arrays in two independent tumour sample sets of CRC patients recruited in 2003–2010 by the German DACHS study (discovery cohort n = 917, replication cohort n = 907). ERβ expr…