Thrombus or tumor? A case report of a rare sarcoma entity: intimal sarcoma of the pulmonary arteries.

BACKGROUND: Tumor embolism is a very rare primary manifestation of cancers and the diagnosis is challenging, especially if located in the pulmonary arteries, where it can mimic nonmalignant pulmonary embolism. Intimal sarcoma is one of the least commonly reported primary tumors of vessels with only a few cases reported worldwide. A typical location of this malignancy is the pulmonary artery. Herein, we present a case report of an intimal sarcoma with primary manifestation in the pulmonary arteries. A 53-year-old male initially presented with dyspnea. On imaging, a pulmonary artery embolism was detected and was followed by thrombectomy of the right ventricular outflow tract, main pulmonary artery trunk, and right pulmonary artery after ineffective lysis therapy. Complementary imaging of the chest and abdomen including a PET-CT scan demonstrated no evidence of a primary tumor. Subsequent pathology assessment suggested an intimal sarcoma further confirmed by DNA methylation based molecular analysis. We initiated adjuvant chemotherapy with doxorubicin. Four months after the completion of adjuvant therapy a follow-up scan revealed a local recurrence without distant metastases. DISCUSSION: Primary pulmonary artery intimal sarcoma (PAS) is an exceedingly rare entity and pathological diagnosis remains challenging. Therefore, the detection of entity-specific molecular alterations is a supporting argument in the diagnostic spectrum. Complete surgical resection is the prognostically most important treatment for intimal cardiac sarcomas. Despite adjuvant chemotherapy, the prognosis of cardiac sarcomas remains very poor. This case of a PAS highlights the difficulty in establishing a diagnosis and the aggressive natural course of the disease. CONCLUSION: In case of atypical presentation of a pulmonary embolism, a tumor originating from the great vessels should be considered. Molecular pathology techniques support in establishing a reliable diagnosis.

Specific T-cell receptor beta-rearrangements of gluten-triggered CD8+ T-cells are enriched in celiac disease patients' duodenal mucosa.

Celiac disease (CeD) is an autoimmune disorder affecting the small intestine with gluten as disease trigger. Infections including Influenza A, increase the CeD risk. While gluten-specific CD4+ T-cells, recognizing HLA-DQ2/DQ8 presented gluten-peptides, initiate and sustain the celiac immune response, CD8+ α/ß intraepithelial T-cells elicit mucosal damage. Here, we subjected TCRs from a cohort of 56 CeD patients and 22 controls to an analysis employing 749 published CeD-related TCRß-rearrangements derived from gluten-specific CD4+ T-cells and gluten-triggered peripheral blood CD8+ T-cells. We show, that in addition to TCRs from gluten-specific CD4+ T-cells, TCRs of gluten-triggered CD8+ T-cells are significantly enriched in CeD duodenal tissue samples. TCRß-rearrangements of gluten-triggered CD8+ T-cells were even more expanded in patients than TCRs from gluten-specific CD4+ T-cells (p < 0.0002) and highest in refractory CeD. Sequence alignments with TCR-antigen databases suggest that a subgroup of these most likely indirectly gluten-triggered TCRs recognize microbial, viral, and autoantigens.

Inflammatory pseudotumor (IPT)-surgical cure of an inflammatory syndrome.

UNLABELLED: We report on four female adolescents, who presented with inflammatory symptoms. Extensive diagnostic workup revealed tumors on different locations. After surgical removal, clinical and laboratory signs of inflammation disappeared rapidly. On histology, the tumors showed a mixture of inflammatory cells characteristic of inflammatory pseudotumors in three of the patients. CONCLUSION: In patients with unclear inflammatory symptoms, inflammatory pseudotumor should be added to the differential diagnosis. WHAT IS KNOWN: • The inflammatory pseudotumor (IPT) is a mostly benign myofibroblastic tumor of the soft tissue and causes inflammatory symptoms. What is new: • IPTs have may wider than hitherto defined histologic features. Removal of IPT is curative.

[Standardized and quality-assured predictive PD-L1 testing in the upper gastrointestinal tract. German version]. / Standardisierte und qualitätsgesicherte prädiktive PD-L1-Testung im oberen Gastrointestinaltrakt.

As a result of the high approval dynamics and the growing number of immuno-oncological therapy concepts, the complexity of therapy decisions and control in the area of carcinomas of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD­1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.

Standardized and quality-assured predictive PD-L1 testing in the upper gastrointestinal tract.

As a result of the high approval dynamics and the growing number of immuno-oncological concepts, the complexity of treatment decisions and control in the area of cancers of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD-1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.

[Plasticity of WNT signaling activity in colorectal cancer]. / Plastizität der WNT-Signalwegaktivität im Kolonkarzinom.

Despite inactivating APC mutations, colorectal cancers express the WNT-effector protein ß-catenin in a heterogeneous pattern, with strong nuclear expression confined to a fraction of tumor cells, often only at the tumor's leading edge. WNT-reporter constructs allow separation of these tumor cells with highest WNT/ß-Catenin activity, which also express high levels of several putative cancer stem cell antigens. Unexpectedly however, these cells do not show exclusive tumorigenicity in xenograft experiments, thus questioning their general stemness phenotype. Instead, there appears to be significant plasticity between both tumor cells with high and low WNT/ß-Catenin activity because both cell types can form tumors which again show mixed populations. Furthermore, WNT/ß-Catenin activity in colon cancer cells can be modulated by MAPK signaling thus revealing a means of how other signaling pathways contribute to WNT signaling plasticity in colon cancer.

Regulation of innate immunity by Nrf2.

The transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) has been mainly investigated as a regulator of redox homeostasis. However, research over the past years has implicated Nrf2 as an important regulator of innate immunity. Here, we discuss the role of Nrf2 in the innate immune response, highlighting the interaction between Nrf2 and major components of the innate immune system. Indeed, Nrf2 has been shown to widely control the immune response by interacting directly or indirectly with important innate immune components, including the toll-like receptors-Nuclear factor kappa B (NF-kB) pathway, inflammasome signaling, and the type-I interferon response. This indicates an essential role for Nrf2 in diseases related to microbial infections, inflammation, and cancer. Yet, further studies are required to determine the exact mechanism underpinning the interactions between Nrf2 and innate immune players in order to allow a better understanding of these diseases and leverage new therapeutic strategies.

Optimizing the use of patients' individual outcome information - Development and usability tests of a Chronic Kidney Disease dashboard.

BACKGROUND: Reporting individual clinical and patient-reported outcomes to patients during consultations may add to patients' disease knowledge and activation and stimulate Shared Decision Making (SDM). These outcomes can be presented over time in a clear way by the means of dashboarding. We aimed to systematically develop a Chronic Kidney Disease (CKD) dashboard designed to support consultations, test its usability and explore conditions for optimal use in practice. METHODS: For development a participatory approach with patients and healthcare professionals (HCPs) from three hospitals was used. Working groups and patient focus groups were conducted to identify needs and inform the dashboard's design. Usability was tested in patient interviews. A focus group with HCPs was held to identify conditions for optimal use of the dashboard in daily practice. RESULTS: A dashboard was developed for CKD patients stage 3b-4 visualizing both clinical and patient-reported outcomes over time for use during consultations and accessible for patients at home. Both HCPs and patients indicated that the dashboard can: motivate patients in their treatment by providing feedback on outcomes over time; improve consultation conversations by enhanced preparation of both HCPs and patients; better inform patients, thereby facilitating shared decision making. HCPs and patients both stated that setting a topic agenda for the consultation together is important in effectively discussing the dashboard during consultations. Moreover, the dashboard should not dominate the conversation. Lastly, findings of the usability tests provided design requirements for optimal user-friendliness and clarity. CONCLUSIONS: Dashboarding can be a valuable way of reporting individual outcome information to patients and their clinicians as findings suggest it may stimulate patient activation and facilitate decision making. Co-creation with patients and HCPs was essential for successful development of the dashboard. Gained knowledge from the co-creation process can inform others wishing to develop similar digital tools for use in clinical practice.

Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

Increase of essential amino acids in the bovine uterine lumen during preimplantation development.

Amino acids (AAs) are crucial for the developing conceptus prior to implantation. To provide insights into the requirements of the bovine embryo, we determined the AA composition of the uterine fluid. At days 12, 15, and 18 post-estrus, the uteri of synchronized pregnant and non-pregnant Simmental heifers were flushed for the analysis of 41 AAs and their derivatives by liquid chromatography-tandem mass spectrometry. The ipsilateral endometrium was sampled for quantitative PCR. In addition to a pregnancy-dependent increase of the essential AAs (P<0.01), we detected elevated concentrations for most non-essential proteinogenic AAs. Histidine (His) and the expression of the His/peptide transporter solute carrier 15A3 (SLC15A3) were significantly increased at day 18 of pregnancy in vivo. In addition, SLC15A3 was predominantly stimulated by trophoblast-derived interferon-τ in stroma cells of an in vitro co-culture model of endometrial cells. Our results show an increased concentration of AAs most likely to optimally provide the elongating pre-attachment conceptus with nutrients.

Comparison of CT colonography, colonoscopy, sigmoidoscopy and faecal occult blood tests for the detection of advanced adenoma in an average risk population.

BACKGROUND AND AIMS: This prospective trial was designed to compare the performance characteristics of five different screening tests in parallel for the detection of advanced colonic neoplasia: CT colonography (CTC), colonoscopy (OC), flexible sigmoidoscopy (FS), faecal immunochemical stool testing (FIT) and faecal occult blood testing (FOBT). METHODS: Average risk adults provided stool specimens for FOBT and FIT, and underwent same-day low-dose 64-multidetector row CTC and OC using segmentally unblinded OC as the standard of reference. Sensitivities and specificities were calculated for each single test, and for combinations of FS and stool tests. CTC radiation exposure was measured, and patient comfort levels and preferences were assessed by questionnaire. RESULTS: 221 adenomas were detected in 307 subjects who completed CTC (mean radiation dose, 4.5 mSv) and OC; 269 patients provided stool samples for both FOBT and FIT. Sensitivities of OC, CTC, FS, FIT and FOBT for advanced colonic neoplasia were 100% (95% CI 88.4% to 100%), 96.7% (82.8% to 99.9%), 83.3% (95% CI 65.3% to 94.4%), 32% (95% CI 14.9% to 53.5) and 20% (95% CI 6.8% to 40.7%), respectively. Combination of FS with FOBT or FIT led to no relevant increase in sensitivity. 12 of 45 advanced adenomas were smaller than 10 mm. 46% of patients preferred CTC and 37% preferred OC (p<0.001). CONCLUSIONS: High-resolution and low-dose CTC is feasible for colorectal cancer screening and reaches sensitivities comparable with OC for polyps >5 mm. For patients who refuse full bowel preparation and OC or CTC, FS should be preferred over stool tests. However, in cases where stool tests are performed, FIT should be recommended rather than FOBT.

Analysis of NTRK expression in gastric and esophageal adenocarcinoma (AGE) with pan-TRK immunohistochemistry.

Small molecule inhibitors such as Larotrectinib have been recently approved in the treatment of patients with fusions of the neurotrophic-tropomyosin receptor tyrosine kinase (NTRK) genes 1-3. These genomic rearrangements have been reported across different tumor subtypes with a high prevalence in rare tumors. However, in gastric and esophageal adenocarcinoma (AGE) NTRK fusions have also been described in a subset of Asian patients. In order to study the prevalence of this alteration in Caucasian patients with AGE we performed immunohistochemistry for pan-NTRK in 438 formalin-fixed paraffin embedded (FFPE) tumor samples. While we found NTRK expression in gastric glands and tumor adjacent nerve tissue, we did not detect this marker in the tumor compartment. Based on our findings NTRK fusions do not seem to play a role in the molecularpathology of Caucasian AEG patients, so that other treatment options are required.

Cortisol, dehydroepiandrosterone sulfate, fatty acids, and their relation in recurrent depression.

BACKGROUND: Alterations in hypothalamic-pituitary-adrenal (HPA)-axis activity, fatty acid metabolism, and their relation have been associated with (recurrent) major depressive disorder (MDD), although conflicting findings exist. AIMS: To determine whether alterations in HPA-axis activity and fatty acids in recurrent MDD remain during remission (i.e. reflect a potential trait factor). Furthermore, to test the association between HPA-axis activity and fatty acids in patients versus controls. METHODS: We cross-sectionally compared 73 remitted unmedicated recurrent MDD patients with 46 matched never-depressed controls. Measurements included salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) (awakening, evening, and after sad mood induction) and erythrocyte fatty acid parameters: (I) three main fatty acids [omega-3 docosahexaenoic acid (DHA), and the omega-3 eicosapentaenoic acid/omega-6 arachidonic acid (EPA/AA)-ratio], and (II) structural fatty acid indices [chain length, unsaturation and peroxidation]. RESULTS: Patients showed higher cortisol awakening responses (p = 0.006) and lower evening cortisol/DHEAS ratios (p = 0.044) compared to matched controls. Fatty acids did not differ between patients and controls, but HPA-axis indicators were significantly associated with fatty acid parameters in both groups (0.001 ≤ p ≤ 0.043). Patients and controls significantly differed in the relations between awakening DHEAS or cortisol/DHEAS ratios and fatty acid parameters, including unsaturation and peroxidation indices (0.001≤ p ≤ 0.034). Significance remained after correction for confounders. CONCLUSIONS: Our results further support alterations in HPA-axis activity, i.e. a lower baseline, but higher responsiveness of awakening cortisol, in remitted medication-free recurrent MDD patients. Furthermore, the relationship between HPA-axis and fatty acids showed significant differences in recurrent MDD patients versus controls. Prospective research is needed to determine the predictive value of this relationship for MDD recurrence.

Long-term outcome of patients with relapsed/refractory B-cell non-Hodgkin lymphoma treated with blinatumomab.

Blinatumomab, the first-in-class CD3/CD19 bispecific T-cell engager antibody construct, has recently been approved for treating patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia. However, the clinical proof of concept of blinatumomab efficacy was initially demonstrated in patients with R/R B-cell non-Hodgkin lymphoma (B-NHL) in the MT103-104 phase 1 dose-escalation and expansion trial (NCT00274742), which defined 60 µg/m2 per day as the maximum tolerated dose (MTD). The clinically most relevant adverse effects were neurologic symptoms and cytokine release syndrome. Currently, there are no data on long-term outcomes and toxicity for B-NHL patients receiving blinatumomab treatment, so we performed a single-center, long-term follow-up analysis of 38 patients who participated in the MT103-104 phase 1 trial. We found no evidence for long-term toxicities, especially no blinatumomab-induced neurocognitive impairments. For the entire study population, the median overall survival (OS) was 4.6 years. Remarkably, patients who had received ≥60 µg/m2 per day and responded to blinatumomab achieved a median OS of 7.7 years. Of note, 6 of the surviving patients treated at the MTD have been treatment-free for more than 7 years. In contrast, patients who were treated at dose levels below the MTD had a median OS of only 1.1 years. These results indicate that 60 µg/m2 per day seems to represent the targeted dose level of blinatumomab required for durable remission in R/R B-NHL. Here, we provide the first clinical evidence that blinatumomab lacks long-term toxicity and has the potential to induce sustained remissions in patients with R/R B-NHL.

CD133 expression is an independent prognostic marker for low survival in colorectal cancer.

Colon cancer cells have previously been demonstrated to contain a subpopulation of CD133+ tumour cells that have the ability to initiate tumour growth and are thus referred to as colon cancer-initiating cells or colon cancer stem cells (CSCs). As CD133 is currently one of the best markers to characterise colon CSCs, we analysed CD133+ tumour cells in colorectal cancer specimens using immunohistochemistry. We show that CD133 detection is specific and that the CD133 antigen is localised on the glandular-luminal surface of colon cancer cells, whereas undifferentiated tumour cells at the front of invasion are CD133-. In addition, CD133+ cells are characterised in situ by lack of CK20 expression, whereas they are positive for EpCAM. Moreover, we show that CD133 expression in colorectal cancer is an independent prognostic marker that correlates with low survival in a stratified patient collective. Our results indicate that in colorectal cancer, the CD133+ tumour cells can be detected by immunohistochemistry, which facilitates their further characterisation in situ.

Impacts of perianal disease and faecal incontinence on quality of life and employment in 1092 patients with inflammatory bowel disease.

BACKGROUND: Patient reported outcomes regarding perianal disease and faecal incontinence in the community-based inflammatory bowel disease population are poorly described. AIMS: To determine the impacts of perianal disease and faecal incontinence on quality of life and employment in inflammatory bowel disease patients. METHODS: For this cross-sectional study, a comprehensive survey was sent out to members of the Dutch National Crohn's and Colitis patient organisation. Validated questionnaires regarding faecal incontinence and active perianal disease were used to estimate its prevalence's. The effect on the quality of life (36-Item Short Form Survey) and on employment status (multivariate binary regression analysis) was assessed in this inflammatory bowel disease population. RESULTS: A total number of 1092 returned questionnaires (58% responders) were used for analysis; 750 respondents (69%) were female; mean age was 47 years (IQR 35-59). In 621 patients (57%) Crohn's disease, in 422 (39%) ulcerative colitis and in 49 (4%) patients unclassifiable inflammatory bowel disease was self-reported. The 114 patients (10%) with a stoma were excluded for continence related analyses. Faecal incontinence was reported in 555 patients (57%), was comparable between the different inflammatory bowel disease diagnoses and affected all 36-Item Short Form Survey subscales adversely (incontinence vs continence: Physical functioning 75 vs 84, P < 0.0001; Limitations due to physical health 49 vs 63, P < 0.0001; Limitations due to emotional problems 49 vs 64, P < 0.0001; Energy/fatigue 47 vs 53, P < 0.0001; Emotional well-being 71 vs 74, P = 0.005; Social functioning 63 vs 73, P < 0.0001; Pain 66 vs 75, P < 0.0001; General health 41 vs 48, P < 0.0001). Active perianal disease was reported in 39% Crohn's disease, 16% ulcerative colitis (84% fissures) and 20% unclassifiable inflammatory bowel disease patients. Faecal incontinence was more common in patients with perianal disease (67% vs 53%, P = 0.003). When correcting for age, disease duration, inflammatory bowel disease-related surgery and faecal incontinence, active perianal disease was independently affecting employment (OR 0.67; 95% CI 0.50-0.91; P = 0.01). CONCLUSIONS: Faecal incontinence and perianal disease are quality of life determining factors. Faecal incontinence needs more attention among clinicians, and development of new (drug) therapies needs to be focussed on perianal disease.

Sertoli-Leydig cell tumours of the ovary and testis: a CGH and FISH study.

We present two malignant cases of Sertoli-Leydig cell tumours (SLCT) of the testis and one ovarian SLCT with benign behaviour. The DNA copy number changes affected chromosome 1, 8, 9p, 10, 11, 12, 16, 19, 22 and X. The present study is the first molecular-cytogenetic analysis of Sertoli-Leydig cell tumours of the testis.

Leydig cell tumors of the testis: a molecular-cytogenetic study based on a large series of patients.

The genetic features of the uncommon Leydig cell tumors (LCT) are largely unknown. Consequently, it is of great importance to elucidate the pathogenesis of testicular germ cell tumors by cytogenetic and molecular biological investigations. The purpose of the present study was the examination of cytogenetic features of these tumors in a large series of LCT. It comprised formalin-fixed, paraffin-embedded tissue samples from 25 LCT to analyze the chromosomal constitution using comparative genomic hybridization (CGH). In most of the studied cases, the aberrant cell population was additionally defined by interphase fluorescence in situ hybridization (I-FISH). Our molecular-cytogenetic study indicates chromosomal imbalances in the majority of our cases (21/25, 84%). The most frequent findings were gain of chromosome X, 19 or 19p and loss on chromosome 8 and 16.

Comparison of leaching tests to determine and quantify the release of inorganic contaminants in demolition waste.

The changes in waste management policy caused by the massive generation of waste materials (e.g. construction and demolition waste material, municipal waste incineration products) has led to an increase in the reuse and recycling of waste materials. For environmental risk assessment, test procedures are necessary to examine waste materials before they can be reused. In this article, results of column and lysimeter leaching tests having been applied to inorganic compounds in a reference demolition waste material are presented. The results show a good agreement between the leaching behaviour determined with the lysimeter unit and the column units used in the laboratory. In view of less time and system requirements compared to lysimeter systems, laboratory column units can be considered as a practicable instrument to assess the time-dependent release of inorganic compounds under conditions similar to those encountered in a natural environment. The high concentrations of elements in the seepage water at the initial stage of elution are reflected by the laboratory column leaching tests. In particular, authorities or laboratories might benefit and have an easy-to-use, but nevertheless reliable, method to serve as a basis for decision-making.