To identify radiological and laboratory hallmarks in patients with primary Sjögren's syndrome (pSS) presenting with spinal cord involvement.
Clinical and laboratory routine parameters were analyzed ...in a retrospective multicenter case series of four patients who developed myelitis associated with pSS. Serological and cerebrospinal fluid (CSF) measurements of pSS associated anti-SSA(Ro)-antibodies were initiated, and CSF neurofilament light chain (NFL) levels were assessed. NFL values were compared with results from 15 sex- and age-matched healthy controls. Radiological assessment was performed using multi-sequence spinal cord magnetic resonance imaging.
Three of the four patients initially developed neurological signs suggestive of myelitis and were subsequently diagnosed with pSS. All patients presented a longitudinal spinal T2-hyperintense lesion in the cervical spinal cord, whereas only two patients showed pleocytosis and oligoclonal bands in the CSF. Median (range) CSF-NFL levels were significantly elevated in patients compared to controls (6672 pg/mL (621-50000) vs. 585 pg/mL (357-729),
= 0.009). One patient showed sustained, highly increased NFL levels (50000 pg/mL) in the initial assessment when radiological signs of axonal injury were still absent. Anti-SSA(Ro)-antibodies were found in the serum of three patients, while two patients additionally presented intrathecal anti-SSA(Ro)-antibody production. Elevated CSF-NFL levels and intrathecal synthesis of anti-SSA(Ro)-antibodies were associated with a relapsing and treatment-resistant disease course.
Inflammatory spinal cord lesions associated with pSS are a rare but serious disease leading to severe disability. NFL and anti-SSA(Ro)-antibodies in CSF might serve as prognostic biomarkers and should be routinely assessed in patients with pSS.
BACKGROUND/AIMSMLK4 (KIAA1804) is the second most frequently mutated kinase in microsatellite stable (MSS) colorectal carcinomas (CRC). This molecule is known to regulate different physiological ...cellular processes, including cell cycle, senescence and apoptosis, and mechanistic evidence has been provided that MLK4 plays a role in carcinogenesis. However, whether this kinase exerts a tumor suppressive role or an oncogenic function is still an object of debate. This study aims to elucidate the role of MLK4 in the pathogenesis of CRC by investigating human tumor specimens. METHODSThis study assessed MLK4 expression levels by immunohistochemistry in surgical tumor samples from 204 early-stage CRC patients and their correlation with various clinical-pathological features and patients' outcomes. In addition, MLK4 mRNA transcription was analysed in an independent cohort of 786 colon cancer samples. RESULTSLoss of MLK4 staining was associated with poor overall (OS) and progression free survival (PFS) in CRC patients during a univariate analysis (OS:101 vs 164 months, p=0.0002; PFS:85 vs 125 months, p=0.0001), as well as in multivariate analysis (OS:HR=1.70; p=0.001; PFS:HR=1,61; p=0.001). This was confirmed by analysis of MLK4 mRNA in the second independent cohort. A subgroup analysis according to KRAS mutation status showed that MLK4 staining was associated with better OS and PFS in KRAS mutated cases (HR=2.77; p=0.0001 and HR=2.31; p=0.0003, respectively) and microsatellite stable tumors (HR=1.87; p=0.002 and HR=1.06; p=0.006) but not in KRAS wildtype and microsatellite unstable tumors. CONCLUSIONBy providing the first report from clinical specimens on the prognostic significance of MLK4, we define an oncogenic loss-of-function of this kinase and suggest a possible role in the interaction with KRAS signaling in determining an aggressive phenotype of CRC. These findings warrant the further investigation of MLK4 in wider cohorts and various clinical settings.
Micro-Abstract To our knowledge, this is the largest number of patients with colorectal cancer and brain metastasis (BM) analyzed to date (n = 228; 134 male 59%; 94 female 41%; median age 63 years). ...Most primary tumors were staged as T3/4, N+, Grade 2. BM occurred 29.2 months after initial diagnosis. Overall survival from the time of first diagnosis was 35.6 months, from the time of metastatatic disease 16.5 months, and from BM 2.0 months. Solitary BM were found in 13.6%. 80.7% of all BM occurred sequentially.
The rarity of primary angiitis of the central nervous system (PACNS) demands diagnostic and prognostic biomarkers. We retrospectively measured Neurofilament light chain (NFL) concentrations in ...cerebrospinal fluid in a severely relapsing PACNS patient at multiple time points during the course of the disease. A marked increase in NFL levels preceding the onset of neuro‐axonal damage and arterial‐vessel abnormalities was observed with magnetic resonance imaging as well as with MR‐ and conventional angiography. Thus, marked elevation of NFL in PACNS seems to occur ahead of definitive radiological abnormalities and might serve as a diagnostic biomarker.
Tumor stem cells play a pivotal role in carcinogenesis and metastatic spread in colorectal cancer (CRC). Olfactomedin 4 (OLFM4) is co‐expressed with the established stem cell marker leucine‐rich ...repeat‐containing G protein‐coupled receptor 5 at the bottom of intestinal crypts and has been suggested as a surrogate for cancer stemness and a biomarker in gastrointestinal tumors associated with prognosis. Therefore, it was the aim of the present study to clarify whether OLFM4 is involved in carcinogenesis and metastatic spread in CRC. We used a combined approach of functional assays using forced OLFM4 overexpression in human CRC cell lines, xenograft mice, and an immunohistochemical approach using patient tissues to investigate the impact of OLFM4 on stemness, canonical Wnt signaling, properties of metastasis and differentiation as well as prognosis. OLFM4 expression correlated weakly with tumor grade in one patient cohort (metastasis collection: p = 0.05; pooled analysis of metastasis collection and survival collection: p = 0.19) and paralleled the expression of differentiation markers (FABP2, MUC2, and CK20) (p = 0.002) but did not correlate with stemness‐associated markers. Further analyses in CRC cells lines as well as xenograft mice including forced overexpression of OLFM4 revealed that OLFM4 neither altered the expression of markers of stemness nor epithelial–mesenchymal transition, nor did OLFM4 itself drive proliferation, migration, or colony formation, which are all prerequisites of carcinogenesis and tumor progression. In line with this, we found no significant correlation between OLFM4 expression, metastasis, and patient survival. In summary, expression of OLFM4 in human CRC seems to be characteristic of differentiation marker expression in CRC but is not a driver of carcinogenesis nor metastatic spread.
Primary Epstein-Barr-Virus (EBV)-associated pulmonary lymphoepithelioma-like carcinoma (LELC) is an aggressive rare cancer. Higher incidences have been observed in Asian sub-populations. Multimodal ...treatment paradigms have emerged as promising novel strategies in the management of advanced NSCLC. In this report, we describe the case of a 34-year-old female patient of Asian origin with a post-partum initial diagnosis of pulmonary LELC. Multimodal treatment with chemoimmunotherapy and hypofractionated irradiation to the primary tumour and main metastatic sites led to a favourable response demonstrating that radiotherapy may potentially augment anti-tumour immunity. To the best of our knowledge, this is the first case report on this novel therapy strategy of multi-site hypofractionated radiotherapy and chemoimmunotherapy for metastatic pulmonary EBV-associated LELC.
The integration of three-way catalysts (TWC) and gasoline particulate filters into a single so-called coated GPF (cGPF) can decrease the necessary packaging volume and costs in exhaust gas ...aftertreatment systems. Similar to classical TWCs, it is possible to introduce advanced coating technologies, in the presented case zoning, which creates zones of high and low washcoat loading, resulting in a filter with an axial non-uniformity of the washcoat distribution. In addition to zoning, a filter can either be coated solely in-wall or have a partially or fully on-wall coating, which leads to a variety of coating configurations. To investigate the impact of the coating configuration, a previously published validated cGPF model is applied to evaluate the pressure drop, high load conversion, and light-off performance of fresh cGPFs. The simulations reveal an enhanced light-off at steady-state conditions if more washcoat is deposited at the front part of the filter or on the inlet channel. Under transient conditions, however, a filter with a catalytic layer on the outlet channel performs best.
•The impact of zoning on pressure drop and on conversion is studied.•Differences between on-wall coating and in-wall coating are investigated.•Zoning can decrease the backpressure while decreasing the light-off temperature.•A systematic study of different coating locations is carried out.
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Coated gasoline particulate filters (cGPFs) can reduce gaseous as well as particulate emissions with the same device. However, their more complex design compared to conventional open monoliths ...requires accurate models in the development phase. We therefore present a new global kinetic model for cGPFs considering standard three-way catalyst reactions and extend it with the impact of lean–rich cycling, referred to as dithering. Submodels are introduced for the oxygen storage and for the extent of oxidation of the active centers. Therefore, the model captures the enhanced conversion of the catalyst under various dithering as well as steady-state conditions. Several steady-state and transient experiments were conducted on a specially equipped dynamic engine test bench in order to calibrate the approach. The proposed model accurately predicts the tailpipe emissions released in a worldwide harmonized light vehicles test procedure driving cycle that is not part of the original calibration data.
The aim of our study was to evaluate the quality of histo- and cytomorphological features of PAXgene-fixed specimens and their suitability for histomorphological classification in comparison to ...standard formalin fixation. Fifteen colon cancer tissues were collected, divided into two mirrored samples and either formalin fixed (FFPE) or PAXgene fixed (PFPE) before paraffin embedding. HE- and PAS-stained sections were scanned and evaluated in a blinded, randomised ring trial by 20 pathologists from Europe and the USA using virtual microscopy. The pathologists evaluated histological grading, histological subtype, presence of adenoma, presence of lymphovascular invasion, quality of histomorphology and quality of nuclear features. Statistical analysis revealed that the reproducibility with regard to grading between both fixation methods was rather satisfactory (weighted kappa statistic (
k
w
) = 0.73 (95 % confidence interval (CI), 0.41–0.94)), with a higher agreement between the reference evaluation and the PFPE samples (
k
w
= 0.86 (95 % CI, 0.67–1.00)). Independent from preservation method, inter-observer reproducibility was not completely satisfactory (
k
w
= 0.60). Histomorphological quality parameters were scored equal or better for PFPE than for FFPE samples. For example, overall quality and nuclear features, especially the detection of mitosis, were judged significantly better for PFPE cases. By contrast, significant retraction artefacts were observed more frequently in PFPE samples. In conclusion, our findings suggest that the PAXgene Tissue System leads to excellent preservation of histomorphology and nuclear features of colon cancer tissue and allows routine morphological diagnosis.
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