Mismatch repair deficiency, chemotherapy and survival for resectable gastric cancer: an observational study from the German staR cohort and a meta-analysis.

PURPOSE: In a post hoc analysis of the MAGIC trial, patients with curatively resected gastric cancer (GC) and mismatch repair (MMR) deficiency (MMRd) had better median overall survival (OS) when treated with surgery alone but worse median OS when treated with additional chemotherapy. Further data are required to corroborate these findings. METHODS: Between April 2013 and December 2018, 458 patients with curatively resected GC, including cancers of the esophagogastric junction Siewert type II and III, were identified in the German centers of the staR consortium. Tumor sections were assessed for expression of MLH1, MSH2, MSH6 and PMS2 by immunohistochemistry. The association between MMR status and survival was assessed. Similar studies published up to January 2021 were then identified in a MEDLINE search for a meta-analysis. RESULTS: MMR-status and survival data were available for 223 patients (median age 66 years, 62.8% male), 23 patients were MMRd (10.3%). After matching for baseline clinical characteristics, median OS was not reached in any subgroup. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd and MMRp had a HR of 0.67 (95% CI 0.13-3.37, P = 0.63) and 1.44 (95% CI 0.66-3.13, P = 0.36), respectively. The meta-analysis included pooled data from 385 patients. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd had an improved OS with a HR of 0.36 (95% CI 0.14-0.91, P = 0.03), whereas those with MMRp had a HR of 1.18 (95% CI 0.89-1.58, P = 0.26). CONCLUSION: Our data support a positive prognostic effect for MMRd in GC patients treated with surgery only and a differentially negative prognostic effect in patients treated with perioperative chemotherapy. MMR status determined by preoperative biopsies may be used as a predictive biomarker to select patients for perioperative chemotherapy in curatively resectable GC.

The future of pathology is digital.

Information, archives, and intelligent artificial systems are part of everyday life in modern medicine. They already support medical staff by mapping their workflows with shared availability of cases' referral information, as needed for example, by the pathologist, and this support will be increased in the future even more. In radiology, established standards define information models, data transmission mechanisms, and workflows. Other disciplines, such as pathology, cardiology, and radiation therapy, now define further demands in addition to these established standards. Pathology may have the highest technical demands on the systems, with very complex workflows, and the digitization of slides generating enormous amounts of data up to Gigabytes per biopsy. This requires enormous amounts of data to be generated per biopsy, up to the gigabyte range. Digital pathology allows a change from classical histopathological diagnosis with microscopes and glass slides to virtual microscopy on the computer, with multiple tools using artificial intelligence and machine learning to support pathologists in their future work.

Development of neurodegeneration in amyotrophic lateral sclerosis: from up or down?

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease associated with neurodegeneration and intracellular pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) positive inclusions. The various clinical symptoms, such as motor disorders and cognitive impairment, reflect the degeneration of certain areas of the nervous system. Since the discovery of the significance of pathological TDP-43 for human disease including ALS, there has been an increasing number of studies reporting on the distribution and severity of neurodegeneration. These have rekindled the old debate about whether the first or second motor neuron is the primary site of degeneration in ALS. To shed light on this question, the following is a review of the relevant neuropathological studies.

Feedback-based Self-improving CNN Algorithm for Breast Cancer Lymph Node Metastasis Detection in Real Clinical Environment.

Digital pathology can be thought of as a model composed of 3 main elements; classification algorithm, Graphical User Interface (GUI) and the pathologists. Currently there is only a one way interaction from the classification algorithm to the pathologist. This paper, proposes an additional backward path which is a new feedback-based method, aimed to improve the performance of the classification algorithms by utilizing the feedback of the pathologists. The GUI developed for this purpose, is aimed to be simple and adaptive to different classification algorithms. The method showed significant improvement in the classification performance of the applied Convolutional Neural Network (CNN) algorithm. The 25% quantile of the probability score of the predictions increased from 0.48 to 0.89 and the median of the data increased from 0.95 to 0.99.

Low skeletal muscle mass outperforms the Charlson Comorbidity Index in risk prediction in patients undergoing pancreatic resections.

INTRODUCTION: Low skeletal muscle mass is a known predictor of morbidity and mortality in patients undergoing major pancreatic surgeries. We sought to combine low skeletal muscle mass with established risk predictors to improve their prognostic capacity for postoperative outcome and morbidity. METHODS: As established parameters to predict preoperative mortality risk for patients, the ASA classification and the Charlson Comorbidity Index (CCI) were used. The Hounsfield Units Average Calculation (HUAC) was measured to define low skeletal muscle mass in 424 patients undergoing pancreatic resections for malignancies. Patients in the lowest sex-adjusted quartile for HUAC were defined as having low skeletal muscle mass (muscle wasting). Multivariable Cox regression analysis was utilized to identify preoperative risk factors associated with postoperative morbidity. RESULTS: Median patient age was 63 years (19-87), 47.9% patients were male, and half the cohort had multiple comorbidities (Charlson Comorbidity Index [CCI]>6, 63.2%), 30-day mortality was 5.8% (n = 25). Median HUAC was 19.78 HU (IQR: 15.94-23.54) with 145 patients (34.2%) having low skeletal muscle mass. Preoperative frailty defined by low skeletal muscle mass was associated with an increased risk for postoperative complications (OR 1.55, CI 95% 0.98-2.45, p = 0.014), and a higher 30-day mortality (HR 5.17, CI 95% 1.57-16.69, p = 0.004). With an AUC of 0.85 HUAC showed the highest predictability for 30-day mortality (CI 95% 0.78-0.91, p = 0.0001). Patients with CCI ≥6 and low skeletal muscle mass defined by the HUAC had a 9.78 higher risk of dying in the immediate postoperative phase (HR 9.78, CI 95% 2.98-12.2, p = 0.0001). CONCLUSION: Low skeletal muscle mass predicts postoperative mortality and complications best and it should be incorporated to conventional risk scores to identify high risk patients.

Rheological characterization of human brain tissue.

The rheology of ultrasoft materials like the human brain is highly sensitive to regional and temporal variations and to the type of loading. While recent experiments have shaped our understanding of the time-independent, hyperelastic response of human brain tissue, its time-dependent behavior under various loading conditions remains insufficiently understood. Here we combine cyclic and relaxation testing under multiple loading conditions, shear, compression, and tension, to understand the rheology of four different regions of the human brain, the cortex, the basal ganglia, the corona radiata, and the corpus callosum. We establish a family of finite viscoelastic Ogden-type models and calibrate their parameters simultaneously for all loading conditions. We show that the model with only one viscoelastic mode and a constant viscosity captures the essential features of brain tissue: nonlinearity, pre-conditioning, hysteresis, and tension-compression asymmetry. With stiffnesses and time constants of µ∞=0.7kPa, µ1=2.0kPa, and τ1=9.7s in the gray matter cortex and µ∞=0.3kPa, µ1=0.9kPa and τ1=14.9s in the white matter corona radiata combined with negative parameters α∞ and α1, this five-parameter model naturally accounts for pre-conditioning and tissue softening. Increasing the number of viscoelastic modes improves the agreement between model and experiment, especially across the entire relaxation regime. Strikingly, two cycles of pre-conditioning decrease the gray matter stiffness by up to a factor three, while the white matter stiffness remains almost identical. These new insights allow us to better understand the rheology of different brain regions under mixed loading conditions. Our family of finite viscoelastic Ogden-type models for human brain tissue is simple to integrate into standard nonlinear finite element packages. Our simultaneous parameter identification of multiple loading modes can inform computational simulations under physiological conditions, especially at low to moderate strain rates. Understanding the rheology of the human brain will allow us to more accurately model the behavior of the brain during development and disease and predict outcomes of neurosurgical procedures. STATEMENT OF SIGNIFICANCE: While recent experiments have shaped our understanding of the time-independent, hyperelastic response of human brain tissue, its time-dependent behavior at finite strains and under various loading conditions remains insufficiently understood. In this manuscript, we characterize the rheology of human brain tissue through a family of finite viscoelastic Ogdentype models and identify their parameters for multiple loading modes in four different regions of the brain. We show that even the simplest model of this family, with only one viscoelastic mode and five material parameters, naturally captures the essential features of brain tissue: its characteristic nonlinearity, pre-conditioning, hysteresis, and tension-compression asymmetry. For the first time, we simultaneously identify a single parameter set for shear, compression, tension, shear relaxation, and compression relaxation loading. This parameter set is significant for computational simulations under physiological conditions, where loading is naturally of mixed mode nature. Understanding the rheology of the human brain will help us predict neurosurgical procedures, inform brain injury criteria, and improve the design of protective devices.

Mechanical characterization of human brain tissue.

Mechanics are increasingly recognized to play an important role in modulating brain form and function. Computational simulations are a powerful tool to predict the mechanical behavior of the human brain in health and disease. The success of these simulations depends critically on the underlying constitutive model and on the reliable identification of its material parameters. Thus, there is an urgent need to thoroughly characterize the mechanical behavior of brain tissue and to identify mathematical models that capture the tissue response under arbitrary loading conditions. However, most constitutive models have only been calibrated for a single loading mode. Here, we perform a sequence of multiple loading modes on the same human brain specimen - simple shear in two orthogonal directions, compression, and tension - and characterize the loading-mode specific regional and directional behavior. We complement these three individual tests by combined multiaxial compression/tension-shear tests and discuss effects of conditioning and hysteresis. To explore to which extent the macrostructural response is a result of the underlying microstructural architecture, we supplement our biomechanical tests with diffusion tensor imaging and histology. We show that the heterogeneous microstructure leads to a regional but not directional dependence of the mechanical properties. Our experiments confirm that human brain tissue is nonlinear and viscoelastic, with a pronounced compression-tension asymmetry. Using our measurements, we compare the performance of five common constitutive models, neo-Hookean, Mooney-Rivlin, Demiray, Gent, and Ogden, and show that only the isotropic modified one-term Ogden model is capable of representing the hyperelastic behavior under combined shear, compression, and tension loadings: with a shear modulus of 0.4-1.4kPa and a negative nonlinearity parameter it captures the compression-tension asymmetry and the increase in shear stress under superimposed compression but not tension. Our results demonstrate that material parameters identified for a single loading mode fail to predict the response under arbitrary loading conditions. Our systematic characterization of human brain tissue will lead to more accurate computational simulations, which will allow us to determine criteria for injury, to develop smart protection systems, and to predict brain development and disease progression. STATEMENT OF SIGNIFICANCE: There is a pressing need to characterize the mechanical behavior of human brain tissue under multiple loading conditions, and to identify constitutive models that are able to capture the tissue response under these conditions. We perform a sequence of experimental tests on the same brain specimen to characterize the regional and directional behavior, and we supplement our tests with DTI and histology to explore to which extent the macrostructural response is a result of the underlying microstructure. Results demonstrate that human brain tissue is nonlinear and viscoelastic, with a pronounced compression-tension asymmetry, and we show that the multiaxial data can best be captured by a modified version of the one-term Ogden model.

Expression pattern of ISL-1, TTF-1 and PAX5 in olfactory neuroblastoma.

Olfactory neuroblastoma (ONB) is a rare neoplasm of the sinonasal area with neuroendocrine differentiation. ISL-1, TTF-1 and PAX5 are transcription factors that are frequently upregulated in tumors showing neuroendocrine differentiation. The aim of our study was to evaluate these markers in a group of ONBs. We included 11 ONBs from 4 large university hospitals. Immunohistochemical expression of TTF-1, PAX5 and ISL-1 was evaluated. TTF-1, ISL-1 and PAX5 were expressed in 3/11 cases (27.27%, h-score: 3-45), 7/11 cases (63.64%, h-score: 23-200), and in 3/11 cases (27.77%, h-score 3-85), respectively. The patient with the strongest PAX5 reactivity exhibited an aggressive clinical course with rapid dissemination to the spine and death shortly after the diagnosis. No significant correlation in the expression of PAX5 and TTF-1 ( = 0.43; p = 0.18) was observed. ISL-1 is widely expressed in tumors with neuroendocrine differentiation and therefore of limited value in their differential diagnosis. TTF-1 positivity does not exclude the diagnosis of primary ONB, although usually only a small percentage of cells are positive. PAX5 expression is infrequent (27.27%) in ONB; however, if present it can be associated with a very aggressive clinical course.

Non-coding RNAs in pancreatic cancer: challenges and opportunities for clinical application.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a dismal prognosis for which new therapeutic strategies are desperately needed. Non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), may yield new therapeutic concepts for the treatment of PDAC. A vast number of miRNAs, including the well-studied miR-21, miR-155 and miR-34, has been shown to regulate PDAC growth, invasion and metastasis in vitro and in vivo by targeting members of key signaling pathways. In addition, other miRNAs and lncRNAs, such as HOTTIP and MALAT-1, have been shown to influence the malignant behavior of PDAC cells. METHODS: Here, we discuss several ncRNAs that may be used either as new therapeutic agents or as targets of new therapeutic agents. Furthermore, we discuss the problem of proper delivery of nucleotide-based agents and novel methods that may be used to circumvent this problem. CONCLUSIONS: Although the number of reports addressing the role of ncRNAs in PDAC virtually grows by the day, there are still many steps to be taken before the application of ncRNA-based therapies will become reality in clinical practice.

GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis.

BACKGROUND AND PURPOSE: Tumour cell migration and adhesion constitute essential features of metastasis. G-protein coupled receptor 55 (GPR55), a lysophospholipid receptor, has been shown to play an important role in carcinogenesis. Here, we investigated the involvement of GPR55 in migration and metastasis of colon cancer cells. EXPERIMENTAL APPROACH: Adhesion and migration assays using the highly metastatic colon cancer cell line HCT116 and an in vivo assay of liver metastasis were performed. The GPR55 antagonist CID16020046, cannabidiol, a putative GPR55 antagonist and GPR55 siRNA were used to block GPR55 activity in HCT116 colon cancer cells. KEY RESULTS: HCT116 cells showed a significant decrease in adhesion to endothelial cells and in migration after blockade with CID16020046 or cannabidiol. The inhibitory effects of CID16020046 or cannabidiol were averted by GPR55 siRNA knock down in cancer cells. The integrity of endothelial cell monolayers was increased after pretreatment of HCT116 cells with the antagonists or after GPR55 siRNA knockdown while pretreatment with lysophosphatidylinositol (LPI), the endogenous ligand of GPR55, decreased integrity of the monolayers. LPI also induced migration in GPR55 overexpressing HCT116 cells that was blocked by GPR55 antagonists. In a mouse model of metastasis, the arrest of HCT116 cancer cells in the liver was reduced after treatment with CID16020046 or cannabidiol. Increased levels of LPI (18:0) were found in colon cancer patients when compared with healthy individuals. CONCLUSIONS AND IMPLICATIONS: GPR55 is involved in the migratory behaviour of colon carcinoma cells and may serve as a pharmacological target for the prevention of metastasis. © 2015 The British Pharmacological Society.

IMP2/p62 induces genomic instability and an aggressive hepatocellular carcinoma phenotype.

Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related deaths and commonly develops in inflammatory environments. The IGF2 mRNA-binding protein IMP2-2/IGF2BP2-2/p62 was originally identified as an autoantigen in HCC. Aim of this study was to investigate a potential pathophysiological role of p62 in hepatocarcinogenesis. Human HCC tissue showed overexpression of IMP2, which strongly correlated with the fetal markers AFP and DLK1/Pref-1/FA-1 and was particularly elevated in tumors with stem-like features and hypervascularization. Molecular classification of IMP2-overexpressing tumors revealed an aggressive phenotype. Livers of mice overexpressing the IMP2 splice variant p62 highly expressed the stem cell marker DLK1 and secreted DLK1 into the blood. p62 was oncogenic: diethylnitrosamine (DEN)-treated p62 transgenic mice exhibited a higher tumor incidence and multiplicity than wild types. Tumors of transgenics showed a more aggressive and stem-like phenotype and displayed more oncogenic chromosomal aberrations determined with aCGH analysis. DEN-treated p62 transgenic mice exhibited distinct signs of inflammation, such as inflammatory cytokine expression and oxidative stress markers, that is, thiobarbituric acid-reactive substance (TBARS) levels. Reactive oxygen species (ROS) production was elevated in HepG2 cells, which either overexpressed p62 or were treated with DLK1. p62 induced this ROS production by a DLK1-dependent induction and activation of the small Rho-GTPase RAC1, activating NADPH oxidase and being overexpressed in human HCC. Our data indicate that p62/IMP2 promotes hepatocarcinogenesis by an amplification of inflammation.

Patatin-like phospholipase 3 (rs738409) gene polymorphism is associated with increased liver enzymes in obese adolescents and metabolic syndrome in all ages.

BACKGROUND: Obesity is associated with non-alcoholic fatty liver disease (NAFLD), and the patatin-like phospholipase 3 (PNPLA3) rs738409 (Ile148Met, C>G) gene polymorphism is one of the most important genetic determinants of NAFLD. Carriers have been reported to better respond to lifestyle modification. AIM: To investigate the effect of rs738409 on overweight/obese adolescents and adults with and without metabolic syndrome (MetS). METHODS: Two hundred and eighty-eight overweight/obese and 209 normal weight participants of the STYJOBS/EDECTA cohort (NCT00482924) were analysed for PNPLA3 genotypes. RESULTS: Compared to overweight/obese without MetS, in overweight/obese study participants with MetS, the presence of the G allele (148Met) was significantly higher (CC: 5.0% vs. 9.2%, Spearman's correlation, 0.12; P = 0.038). Persons with CG (heterozygote for the risk allele) and with GG (homozygote for the risk allele) genotypes showed significantly higher ALT levels than those with CC genotypes. Even young individuals aged below 20 years had significantly increased ALT levels if they were homozygote with the G allele. CONCLUSIONS: The PNPLA3 rs738409 polymorphism is associated already in youths with increased ALT, and is more frequent in obese with MetS of all ages. Hence, overweight/obese rs738409 carriers should be identified early in life and treated with a rigorous life style intervention.

Higher strains in the inner region of the meniscus indicate a potential source for degeneration.

Complex structural properties of menisci can be characterized in part by their inhomogeneous strain response under compression. This pilot study explored the feasibility to quantify characteristic strain distributions on meniscus cross-sections subjected to static compression using electronic speckle pattern interferometry (ESPI). Cross-sectional specimens of 5-mm thickness were harvested from eight human menisci. After application of 20% pre-strain, strain maps in response to 10µm compression were captured with ESPI. The 10µm compression induced an aggregate strain of nominally 0.14% and resulted in highly non-uniform strain distributions. Local compressive strain captured by ESPI ranged from 0.03% to 0.7%. The highest strain was in the central region of meniscus cross-sections, and the lowest magnitude of strain was at the femoral surface of the meniscus. After stratifying for age, peak compressive strain in older menisci (71±6 years, n=4) was 0.33%±0.09, compared to 0.25%±0.06 in younger menisci (34±9 years, n=4). In conclusion, this study captured for the first time continuous strain distribution maps over entire meniscus cross-sections. The non-uniform strain distributions demonstrated inhomogeneous structural properties. Age-related differences in characteristic strain distributions likely represent degenerative changes. As such, ESPI provides a novel strategy of further characterize meniscal function and degeneration.

Relative survival of patients with non-malignant central nervous system tumours: a descriptive study by the Austrian Brain Tumour Registry.

BACKGROUND: Unlike malignant primary central nervous system (CNS) tumours outcome data on non-malignant CNS tumours are scarce. For patients diagnosed from 1996 to 2002 5-year relative survival of only 85.0% has been reported. We investigated this rate in a contemporary patient cohort to update information on survival. METHODS: We followed a cohort of 3983 cases within the Austrian Brain Tumour Registry. All patients were newly diagnosed from 2005 to 2010 with a histologically confirmed non-malignant CNS tumour. Vital status, cause of death, and population life tables were obtained by 31 December 2011 to calculate relative survival. RESULTS: Overall 5-year relative survival was 96.1% (95% CI 95.1-97.1%), being significantly lower in tumours of borderline (90.2%, 87.2-92.7%) than benign behaviour (97.4%, 96.3-98.3%). Benign tumour survival ranged from 86.8 for neurofibroma to 99.7% for Schwannoma; for borderline tumours survival rates varied from 83.2 for haemangiopericytoma to 98.4% for myxopapillary ependymoma. Cause of death was directly attributed to the CNS tumour in 39.6%, followed by other cancer (20.4%) and cardiovascular disease (15.8%). CONCLUSION: The overall excess mortality in patients with non-malignant CNS tumours is 5.5%, indicating a significant improvement in survival over the last decade. Still, the remaining adverse impact on survival underpins the importance of systematic registration of these tumours.

Report from the OECI Oncology Days 2014.

The 2014 OECI Oncology Days was held at the 'Prof. Dr. Ion Chiricuta' Oncology Institute in Cluj, Romania, from 12 to 13 June. The focus of this year's gathering was on developments in personalised medicine and other treatment advances which have made the cost of cancer care too high for many regions throughout Europe.

Low expression of the putative tumour suppressor spinophilin is associated with higher proliferative activity and poor prognosis in patients with hepatocellular carcinoma.

BACKGROUND: Spinophilin, a multifunctional intracellular scaffold protein, is reduced in certain types of cancer and is regarded as a novel putative tumour suppressor protein. However, the role of spinophilin in hepatocellular carcinoma (HCC) has never been explored before. METHODS: In this study, we determined for the first time the expression pattern of spinophilin in human HCC by immunohistochemistry and quantitative reverse transcriptase-PCR analysis. In addition, we performed immunohistochemical analysis of p53, p14(ARF) and the proliferation marker Ki-67. Kaplan-Meier curves and multivariate Cox proportional models were used to study the impact on clinical outcome. Small interfering RNA (siRNA) was used to silence spinophilin and to explore the effects of reduced spinophilin expression on cellular growth. RESULTS: In our study, complete loss of spinophilin immunoreactivity was found in 44 of 104 HCCs (42.3%) and reduced levels were found in an additional 37 (35.6%) cases. After adjusting for other prognostic factors, multivariate Cox regression analysis identified low expression of spinophilin as an independent prognostic factor with respect to disease-free (hazard ratio (HR)=1.8; 95% confidence interval (CI)=1.04-3.40; P=0.043) and cancer-specific survival (HR=2.0; CI=1.1-3.8; P=0.025). Reduced spinophilin expression significantly correlated with higher Ki-67 index in HCC (P=0.014). Reducing spinophilin levels by siRNA induced a higher cellular growth rate and increased cyclin D2 expression in tumour cells (P<0.05). CONCLUSION: This is the first study of the expression pattern and distribution of spinophilin in HCC. According to our data, the loss of spinophilin is associated with higher proliferation and might be useful as a prognostic marker in patients with HCC.

Expression of nogo-a is decreased with increasing gestational age in the human fetal brain.

Nogo is a member of the reticulon family. Our understanding of the physiological functions of the Nogo-A protein has grown over the last few years, and this molecule is now recognized as one of the most important axonal regrowth inhibitors present in central nervous system (CNS) myelin. Nogo-A plays other important roles in nervous system development, epilepsy, vascular physiology, muscle pathology, stroke, inflammation, and CNS tumors. Since the exact role of Nogo-A protein in human brain development is still poorly understood, we studied its cellular and regional distribution by immunohistochemistry in the frontal lobe of 30 human fetal brains. Nogo-A was expressed in the following cortical zones: ependyma, ventricular zone, subventricular zone, intermediate zone, subplate, cortical plate, and marginal zone. The number of positive cells decreased significantly with increasing gestational age in the subplate and marginal zone. Using different antibodies, changes in isoform expression and dimerization states could be shown between various cortical zones. The results demonstrate a significant change in the expression of Nogo-A during the development of the human brain. The effects of its time- and region-specific regulation have to be further studied in detail.