Comprehensive frailty assessment with multidimensional frailty domains as a predictor of mortality among vascular and cardiac surgical patients.

Purpose: The frailty concept has become a fundamental part of daily clinical practice. In this study our purpose was to create a risk estimation method with a comprehensive aspect of patients' preoperative frailty. Patients and methods: In our prospective, observational study, patients were enrolled between September 2014 and August 2017 in the Department of Cardiac Surgery and Department of Vascular Surgery at Semmelweis University, Budapest, Hungary. A comprehensive frailty score was built from four main domains: biological, functional-nutritional, cognitive-psychological and sociological. Each domain contained numerous indicators. In addition, the EUROSCORE for cardiac patients and the Vascular POSSUM for vascular patients were calculated and adjusted for mortality. Results: Data from 228 participants were included for statistical analysis. A total of 161 patients underwent vascular surgery, and 67 underwent cardiac surgery. The preoperatively estimated mortality was not significantly different (median: 2.700, IQR (interquartile range): 2.000-4.900 vs. 3.000, IQR: 1.140-6.000, P = 0.266). The comprehensive frailty index was significantly different (0.400 (0.358-0.467) vs. 0.348 (0.303-0.460), P = 0.001). In deceased patients had elevated comprehensive frailty index (0.371 (0.316-0.445) vs. 0.423 (0.365-0.500), P < 0.001). In the multivariate Cox model an increased risk for mortality in quartiles 2, 3 and 4 compared with quartile 1 as a reference was found (AHR (95% CI): 1.974 (0.982-3.969), 2.306 (1.155-4.603), and 3.058 (1.556-6.010), respectively). Conclusion: The comprehensive frailty index developed in this study could be an important predictor of long-term mortality after vascular or cardiac surgery. Accurate frailty estimation could make the traditional risk scoring systems more accurate and reliable.

Mapping Immune Correlates and Surfaceome Genes in BRAF Mutated Colorectal Cancers.

Despite the impressive results obtained with immunotherapy in several cancer types, a significant fraction of patients remains unresponsive to these treatments. In colorectal cancer (CRC), B-RafV600 mutations have been identified in 8-15% of the patients. In this work we interrogated a public dataset to explore the surfaceome of these tumors and found that several genes, such as GP2, CLDN18, AQP5, TM4SF4, NTSR1, VNN1, and CD109, were upregulated. By performing gene set enrichment analysis, we also identified a striking upregulation of genes (CD74, LAG3, HLA-DQB1, HLA-DRB5, HLA-DMA, HLA-DMB, HLA-DPB1, HLA-DRA, HLA-DOA, FCGR2B, HLA-DQA1, HLA-DRB1, and HLA-DPA1) associated with antigen processing and presentation via MHC class II. Likewise, we found a strong correlation between PD1 and PD(L)1 expression and the presence of genes encoding for proteins involved in antigen presentation such as CD74, HLA-DPA1, and LAG3. Furthermore, a similar association was observed for the presence of dendritic cells and macrophages. Finally, a low but positive relationship was observed between tumor mutational burden and neoantigen load. Our findings support the idea that a therapeutic strategy based on the targeting of PD(L)1 together with other receptors also involved in immuno-modulation, such as LAG3, could help to improve current treatments against BRAF-mutated CRC tumors.

Evaluation of a transbronchial cryoprobe for the ablation of pulmonary nodules: an in vitro pilot study.

BACKGROUND: Ablation of malignant pulmonary nodules is a novel therapeutic option for patients who cannot undergo surgery. Current transthoracic approaches cause pneumothorax and/or bleeding in a significant number of cases. OBJECTIVE: Our purpose with this study was to evaluate cryoablation under in vitro conditions with a commercially available cryosurgery system. METHODS: We used ballistic gelatin to model the thermal conduction of lung tissue. The cryoprobe was inserted in the ballistic gelatin with two thermal sensors, they were placed 0.5 cm and 1.0. cm from the probe, respectively, temperature was measured on both sides. We used single-, double- and triple-freeze protocols to see if we could freeze it to -20 °C. RESULTS: We achieved - 18.6 ± 3.26 °C on the closer sensor (sensor 1) and - 3.7 ± 4.61 °C on the sensor further away (sensor 2) after 15 min using the single-freeze protocol. Using the dual-freeze protocol, we achieved - 23.2 ± 2,23 °C on sensor 1 and - 16.5 ± 2.82 °C on sensor 2. With the triple-freeze protocol we obtained - 23.5 ± 2.38 °C on sensor 1 and - 19.05 ± 3.22 °C on sensor 2. CONCLUSION: With dual-freeze, values above - 20 °C were achieved using nearer sensor data, but a plateau phase occurred as with continuous freezing. Using triple freeze, we reached - 20 °C at a distance of 0.5 cm from the probe, but not at 1 cm; therefore, we did not expand the diameter of the predicted necrosis zone.

Association between Hepatic Venous Congestion and Adverse Outcomes after Cardiac Surgery.

INTRODUCTION: Hepatic venous flow patterns reflect pressure changes in the right ventricle and are also markers of systemic venous congestion. Fluid management is crucial in patients undergoing cardiac surgery. METHODS: Our goal was to determine which factors are associated with the increased congestion of the liver as measured by Doppler ultrasound in patients undergoing cardiac surgery. This prospective, observational study included 41 patients without preexisting liver disease who underwent cardiac surgery between 1 January 2021 and 30 September 2021 at a tertiary heart center. In addition to routine echocardiographic examination, we recorded the maximal velocity and velocity time integral (VTI) of the standard four waves seen in the common hepatic vein (flow profile) using Doppler ultrasound preoperatively and at the 20-24th hour of the postoperative period. The ratios of the retrograde and anterograde hepatic venous waves were calculated, and the waveforms were compared to the baseline value and expressed as a delta ratio. Demographic data, pre- and postoperative echocardiographic parameters, intraoperative variables (procedure, cardiopulmonary bypass time), postoperative factors (fluid balance, vasoactive medication requirement, ventilation time and parameters) and perioperative laboratory parameters (liver and kidney function tests, albumin) were used in the analysis. RESULTS: Of the 41 patients, 20 (48.7%) were males, and the median age of the patients was 65.9 years (IQR: 59.8-69.9 years). Retrograde VTI growth showed a correlation with positive fluid balance (0.89 (95% CI 0.785-0.995) c-index. After comparing the postoperative echocardiographic parameters of the two subgroups, right ventricular and atrial diameters were significantly greater in the "retrograde VTI growth" group. The ejection fraction and decrement in ejection fraction to preoperative parameters were significantly different between the two groups. (p = 0.001 and 0.003). Ventilation times were longer in the retrograde VTI group. The postoperative vs. baseline delta VTI ratio of the hepatic vein correlated with positive fluid balance, maximum central venous pressure, and ejection fraction. (B = -0.099, 95% CI = -0.022-0.002, p = 0.022, B = 0.011, 95% CI = 0.001-0.021, p = 0.022, B = 0.091, 95% CI = 0.052-0.213, p = 0.002, respectively.) Conclusion: The increase of the retrograde hepatic flow during the first 24 h following cardiac surgery was associated with positive fluid balance and the decrease of the right ventricular function. Measurement of venous congestion or venous abdominal insufficiency seems to be a useful tool in guiding fluid therapy and hemodynamic management.

[Case report: molecular analysis of congenital glioblastoma in a newborn]. / Esettanulmány: molekuláris vizsgálatok újszülöttkori glioblasztómában.

BACKGROUND: Congenital glioblastoma (cGBM) is a brain tumor very rarely observed in newborns and young infants, and differs in several respects from glioblastoma (GBM) of childhood and adulthood. Our aim was the presentation of a cGBM case with 14 days of postnatal survival at the Pediatric Oncology Center of the Markusovszky University Teaching Hospital in 2004. We investigated formalin-fixed, paraffin-embedded autoptic tumor samples of the newborn by immunohistochemical and molecular genetic (FISH and pyrosequencing) methods. We found polysomy of chromosome 2 and 5' deletion of the ALK gene in the glioma cells by ALK FISH. This result indicates the importance of molecular analyses in the diagnostic evaluation of cGBM, and raises the possibility of a personalized, targeted therapy (crizotinib, alectinib).

Distally Tilted Implants According to the All-on-Four® Treatment Concept for the Rehabilitation of Complete Edentulism: A 3.5-Year Retrospective Radiographic Study of Clinical Outcomes and Marginal Bone Level Changes.

Bone grafting procedures during the use of dental implants may be avoided by the use of tilted implants in the maxilla and the mandible; advantages of angled implants are associated with the extension of the distal cantilever, leading to better implant survival rates. However, the bending effect on the single tilting implants may increase the marginal bone stress. The purpose of the present study was to retrospectively assess the clinical success and proximal bone loss rate following the implantation of distally tilted implants according to the All-on-Four™ prosthetic concept­based on radiographic findings­in a single-center experience, in addition to the assessment of the outcomes in the context of various clinico-epidemiological correlates. During the study period, n = 36 patients (24 males and 12 females) with complete records of periapical radiographs, received a full-arch fixed bridge supported by two axial and two distal tilted implants; overall n = 144 and n = 144 implants (Nobel B) were place in the maxilla and mandibles of patients, respectively. Mean age of patients at the time of fixture installation was 58.75 ± 13.71 years; n =11 patients presented with relevant underlying conditions/habits. To assess peri-implant bone-level changes, matched and calibrated orthopantomogram (OPT) images were taken at follow-ups after 1.5 years, 2.5 years, and 3.5 years post-restoration, and marginal bone levels were assessed on the mesio- (MA) and disto-approximal (DA) aspects. All implants were successful, resulting in a 100% overall survival rate. The radiographic mean bone loss levels at baseline (mean ± SEM) were 0.181 ± 0.011 mm and 0.178 ± 0.017 mm in the maxilla and mandible, respectively, while by the 3.5-year mark, bone loss was 0.770 ± 0.029 mm and 0.713 ± 0.026 mm in the maxilla and mandible (p > 0.05), respectively; bone-level changes were significant over time (p = 0.035 and p = 0.033). Peri-implant bone loss was more aggressive around titled distal implants versus mesial actual position implants. The effect of smoking and other underlying conditions showed significantly higher (p < 0.05) bone resorption levels when assessed on an individual implant-level, while during patient-level analysis, only a tendency was shown for higher bone loss rates for both MA and DA implants (p > 0.05). Within its limitations, our study has concluded that the use of All-on-Four™ prosthetic concept for total arch rehabilitation yields higher bone loss in association with tilted implants and, in some cases, on the MA surfaces at vertically positioned implants after >40 months in function.

Association between Preoperative Retrograde Hepatic Vein Flow and Acute Kidney Injury after Cardiac Surgery.

Key questions: Is there a predictive value of hepatic venous flow patterns for postoperative acute kidney injury (AKI) after cardiac surgery? Key findings: In patients who underwent cardiac surgery, retrograde hepatic venous waves (A, V) and their respective ratio to anterograde waves showed a strong association with postoperative AKI, defined as the percentage change of the highest postoperative serum creatinine from the baseline preoperative concentration (%ΔCr). The velocity time integral (VTI) of the retrograde A wave and the ratio of the retrograde and anterograde waves' VTI were independently associated with AKI after adjustment for disease severity. Take-home message: A higher ratio of retrograde/antegrade waves in hepatic venous retrograde waves, which are related to hepatic stasis, may predict AKI after cardiac surgery. Introduction: Hepatic venous flow patterns reflect pressure changes in the right ventricle and are also markers of systemic venous congestion. Pulsatility of the inferior caval vein was used to predict the risk of acute kidney injury (AKI) after cardiac surgery. Aims: Our objective was to evaluate the association between preoperative hepatic venous flow patterns and the risk of AKI in patients after cardiac surgery. Methods: This prospective, observational study included 98 patients without preexisting liver disease who underwent cardiac surgery between 1 January 2018, and 31 March 2020, at a tertiary heart center. In addition to a routine echocardiographic examination, we recorded the maximal velocity and velocity time integral (VTI) of the standard four waves in the common hepatic vein with Doppler ultrasound. Our primary outcome measure was postoperative AKI, defined as the percentage change of the highest postoperative serum creatinine from the baseline preoperative concentration (%ΔCr). The secondary outcome was AKI, defined by KDIGO (Kidney Disease Improving Global Outcomes) criteria. Results: The median age of the patients was 69.8 years (interquartile range [IQR 25−75] 13 years). Seventeen patients (17.3%) developed postoperative AKI based on the KDIGO. The VTI of the retrograde A waves in the hepatic veins showed a strong correlation (B: 0.714; p = 0.0001) with an increase in creatinine levels after cardiac surgery. The velocity time integral (VTI) of the A wave (B = 0.038, 95% CI = 0.025−0.051, p < 0.001) and the ratio of VTI of the retrograde and anterograde waves (B = 0.233, 95% CI = 0.112−0.356, p < 0.001) were independently associated with an increase in creatinine levels. Conclusions: The severity of hepatic venous regurgitation can be a sign of venous congestion and seems to be related to the development of AKI.

Primary Founder Mutations in the PRKDC Gene Increase Tumor Mutation Load in Colorectal Cancer.

The clonal composition of a malignant tumor strongly depends on cellular dynamics influenced by the asynchronized loss of DNA repair mechanisms. Here, our aim was to identify founder mutations leading to subsequent boosts in mutation load. The overall mutation burden in 591 colorectal cancer tumors was analyzed, including the mutation status of DNA-repair genes. The number of mutations was first determined across all patients and the proportion of genes having mutation in each percentile was ranked. Early mutations in DNA repair genes preceding a mutational expansion were designated as founder mutations. Survival analysis for gene expression was performed using microarray data with available relapse-free survival. Of the 180 genes involved in DNA repair, the top five founder mutations were in PRKDC (n = 31), ATM (n = 26), POLE (n = 18), SRCAP (n = 18), and BRCA2 (n = 15). PRKDC expression was 6.4-fold higher in tumors compared to normal samples, and higher expression led to longer relapse-free survival in 1211 patients (HR = 0.72, p = 4.4 × 10-3). In an experimental setting, the mutational load resulting from UV radiation combined with inhibition of PRKDC was analyzed. Upon treatments, the mutational load exposed a significant two-fold increase. Our results suggest PRKDC as a new key gene driving tumor heterogeneity.

Mini-thoracotomy in redo mitral valve surgery: safety and efficacy of a standardized procedure.

BACKGROUND: Re-operative mitral valve surgery is sometimes burdened by a greater technical difficulty and a higher complications rate than the first operation. Minimally invasive cardiac surgery has become routine, and it could significantly reduce the surgical risk in redo surgery. The objective of our retrospective observational study is to assess the results of cardiac reoperations in patients with mitral valve disease approached trough a 5-7 cm right mini-thoracotomy. METHODS: From February 2017 to December 2019, 65 patients underwent re-operative mitral valve surgery in our institution. Cardiopulmonary bypass (CPB) was started by cannulation of the femoral and jugular vein and femoral artery or alternatively right axillary artery. Patients enrolled had a mean age of 66.6±11.5 years. Patients were divided into three groups based on the procedure adopted: external aortic cross-clamp (EAC), EndoAortic balloon occlusion (EABO) and ventricular fibrillation (VF). Major complications were evaluated and compared with a propensity matched population of patients undergoing elective isolated mitral valve surgery via right minithoracotomy (MVS). RESULTS: The average time between last operation and reoperation was 7.1±3.4 years. Fourteen patients (21%) underwent mitral valve repair and 51 patients (78%) underwent mitral valve replacement; 9 patients (14%) received tricuspid valve surgery. There was no statistically significant difference in CPB time between the groups. Seven patients (11%) had a postoperative renal failure, 5 patients (8%) underwent surgical reopening for bleeding; incidence of post-operative stroke and pace-maker implantation was 3% for both. No deaths were registered during in-hospital stay and at 30-days echocardiographic control all patients respect the criterions of device success according with MVARC. Propensity matched patients of group redo had a longer CPB time (100.8±42.7 versus 72.8±16.7 min, P<0.001) and cross-clamp time (71.9±30.7 versus 59±10.7 min, P<0.001) respect to first operation mitral valve surgery patients. CONCLUSIONS: Minimally invasive mitral valve redo surgery is a safe procedure. Less invasive techniques in redo surgery could minimize morbidity and mortality without prolonging the duration of CPB.

Preoperative nutritional state is associated with mid- and long-term mortality after cardiac surgery.

BACKGROUND: The frailty score has been developed to determine physiological functioning capacity. The aim of our research was to explore the relationship between frailty factors and mortality in cardiac surgery patients. METHODS: Our research is an observational, single-center, prospective cohort study (registered on ClinicalTrials.gov: NCT02224222), and we studied 69 patients who underwent elective cardiac surgery between 2014 and 2017. Thirty days before the surgery, they completed a questionnaire that contained questions related to social support, self-reported life quality-happiness, cognitive functions, anxiety and depression. Demographic, anthropometric and medical data were widely collected. The Geriatric Nutritional Risk Index (GNRI) and the Comprehensive Geriatric Assessment (CGA)-based frailty index were calculated as a sum and the domains, respectively. Cox regression and the Kaplan-Meier tests were applied to analyze survival and relative risk. The primary outcome was mid-term mortality. RESULTS: The patients' mean age was 65.43 years [standard deviation (SD): 9.81 years]. The median follow-up was 1,656 days of survival [interquartile range (IQR), 1,336-2,081 years], during this period 14 patients died. The median of EuroSCORE II was 1.56 (1.00-2.58) points. The median preoperative albumin level was 32.80 g/L (IQR, 29.9-35.8 g/L). Major adverse cardiovascular and cerebral events (MACCEs) occurred 7 times during follow-up. The nutrition score of the CGA was significantly associated with worse long-term survival [score; hazard ratio (HR): 5.35; 95% CI: 1.10-25.91, P=0.037]. After adjustment for EuroSCORE II and postoperative complications the noncardiovascular CGA score was associated with overall mortality [adjusted hazard ratio (AHR): 1.44, 95% CI: 1.02-2.04, P=0.036]. In the multivariable Cox regression, GNRI <91 showed an increased risk for mortality (AHR: 4.76, 95% CI: 1.52-14.92, P=0.007). CONCLUSIONS: The CGA-based noncardiovascular score and nutritional status should be assessed before cardiac surgery prehabilitation and may help decrease long-term mortality.

Wnt pathway markers in low-grade and high-grade gliomas.

BACKGROUND AND PURPOSE: Aberrant activation of the Wnt pathway contributes to differentiation and maintenance of cancer stem cells underlying gliomagenesis. The aim of our research was to determine as to what degrees some Wnt markers are expressed in gliomas of different grades, lineages and molecular subtypes. METHODS: Nine grade II, 10 grade III and 72 grade IV surgically removed, formalin-fixed paraffin-embedded glioma specimens were included. Mutation status of IDH1 codon 132 was defined by immunohistochemistry and pyrosequencing in all tumors. Grade II and III astrocytic and oligodendroglial tumors were further tested for the expression of p53 and ATRX by immunohistochemistry, and codeletion of 1p19q by fluorescent in situ hybridization. Expression levels of the non-canonical Wnt5a and Fzd2, and the canonical Wnt3a and beta-catenin Wnt pathway markers were determined by immunohistochemistry, and compared between subgroups stratified according to grade, lineage and the presence or absence of IDH1 R132H/C mutations. RESULTS: In the normal brain - grade II-IV glioma comparisons, a gradual increase was observed for the expressions of Wnt5a, Wnt3a, Fzd2 and beta-catenin. In the astroglial and oligodendroglial lineages of grade II and III gliomas, only the Wnt5a expression was significantly higher in the astroglial subgroup. Stratification according to the IDH1 status resulted in a significant increase of the Wnt3 expression in the wild type grade II-IV gliomas. CONCLUSION: These data extend previous observations and show a correlation of Wnt pathway activity with glioma grade. Further investigations of the Wnt marker expression regulation according to glioma lineage or IDH gene mutational status are in progress by using more exact molecular approaches.

Pancancer survival analysis of cancer hallmark genes.

Cancer hallmark genes are responsible for the most essential phenotypic characteristics of malignant transformation and progression. In this study, our aim was to estimate the prognostic effect of the established cancer hallmark genes in multiple distinct cancer types. RNA-seq HTSeq counts and survival data from 26 different tumor types were acquired from the TCGA repository. DESeq was used for normalization. Correlations between gene expression and survival were computed using the Cox proportional hazards regression and by plotting Kaplan-Meier survival plots. The false discovery rate was calculated to correct for multiple hypothesis testing. Signatures based on genes involved in genome instability and invasion reached significance in most individual cancer types. Thyroid and glioblastoma were independent of hallmark genes (61 and 54 genes significant, respectively), while renal clear cell cancer and low grade gliomas harbored the most prognostic changes (403 and 419 genes significant, respectively). The eight genes with the highest significance included BRCA1 (genome instability, HR 4.26, p < 1E-16), RUNX1 (sustaining proliferative signaling, HR 2.96, p = 3.1E-10) and SERPINE1 (inducing angiogenesis, HR 3.36, p = 1.5E-12) in low grade glioma, CDK1 (cell death resistance, HR = 5.67, p = 2.1E-10) in kidney papillary carcinoma, E2F1 (tumor suppressor, HR 0.38, p = 2.4E-05) and EREG (enabling replicative immortality, HR 3.23, p = 2.1E-07) in cervical cancer, FBP1 (deregulation of cellular energetics, HR 0.45, p = 2.8E-07) in kidney renal clear cell carcinoma and MYC (invasion and metastasis, HR 1.81, p = 5.8E-05) in bladder cancer. We observed unexpected heterogeneity and tissue specificity when correlating cancer hallmark genes and survival. These results will help to prioritize future targeted therapy development in different types of solid tumors.

Biomechanical properties of the bone during implant placement.

BACKGROUND: In this research the biomechanical properties of a bone model was examined. Porcine ribs are used as experimental model. The objective of this research was to investigate and compare the biomechanical properties of the bone model before and after implant placement. METHODS: The bone samples were divided in three groups, Group 1 where ALL-ON-FOUR protocol was used during pre-drilling and placing the implants, Group 2 where ALL-ON-FOUR protocol was used during pre-drilling, and implants were not placed, and Group 3 consisting of intact bones served as a control group. Static and dynamic loading was applied for examining the model samples. Kruskal-Wallis statistical test and as a post-hoc test Mann-Whitney U test was performed to analyze experimental results. RESULTS: According to the results of the static loading, there was no significant difference between the implanted and original ribs, however, the toughness values of the bones decreased largely on account of predrilling the bones. The analysis of dynamic fatigue measurements by Kruskal-Wallis test showed significant differences between the intact and predrilled bones. CONCLUSION: The pre-drilled bone was much weaker in both static and dynamic tests than the natural or implanted specimens. According to the results of the dynamic tests and after a certain loading cycle the implanted samples behaved the same way as the control samples, which suggests that implantation have stabilized the skeletal bone structure.

The effect of cognitive dysfunction on mid- and long-term mortality after vascular surgery.

BACKGROUND: In recent decades, previous studies have noted the importance of frailty, which is a frequently used term in perioperative risk evaluations. Psychological and socioeconomical domains were investigated as part of frailty syndrome. The aim of this study was to assess the importance of these factors in mortality after vascular surgery. METHODS: In our prospective, observational study (ClinicalTrials.gov Identifier: NCT02224222), we examined 164 patients who underwent elective vascular surgery between 2014 and 2017. At the outpatient anaesthesiology clinic, patients completed a questionnaire about cognitive functions, depression and anxiety, social support and self-reported quality of life were assessed using a comprehensive frailty index, in addition to medical variables. Propensity score matching was performed to analyse the difference between patients and controls in a nationwide population cohort. The primary outcome was 4 year mortality. The Kaplan-Meier method and Cox regression analysis were used for statistical analyses. RESULTS: The patients' mean age was 67.05 years (SD: 9.49 years). Mini-Mental State Examination scores of less than 27 points were recorded for 41 patients. Overall mortality rates were 22.4 and 47.6% in the control and cognitive impairment groups, respectively (p = 0.013). In the univariate Cox regression analysis, cognitive impairment measured using age- and education-adjusted MMSE scores increased the risk of mortality (AHR: 2.842, 95% CI: 1.389-5.815, p = 0.004). CONCLUSION: Even mild cognitive dysfunction measured preoperatively using the MMSE represents a potentially important risk factor for mortality after vascular surgery.

muTarget: A platform linking gene expression changes and mutation status in solid tumors.

Large oncology repositories have paired genomic and transcriptomic data for all patients. We used these data to perform two independent analyses: to identify gene expression changes related to a gene mutation and to identify mutations altering the expression of a selected gene. All data processing steps were performed in the R statistical environment. RNA-sequencing and mutation data were acquired from The Cancer Genome Atlas (TCGA). The DESeq2 algorithm was applied for RNA-seq normalization, and transcript variants were annotated with AnnotationDbi. MuTect2-identified somatic mutation data were utilized, and the MAFtools Bioconductor program was used to summarize the data. The Mann-Whitney U test was used for differential expression analysis. The established database contains 7876 solid tumors from 18 different tumor types with both somatic mutation and RNA-seq data. The utility of the approach is presented via three analyses in breast cancer: gene expression changes related to TP53 mutations, gene expression changes related to CDH1 mutations and mutations resulting in altered progesterone receptor (PGR) expression. The breast cancer database was split into equally sized training and test sets, and these data sets were analyzed independently. The highly significant overlap of the results (chi-square statistic = 16 719.7 and P < .00001) validates the presented pipeline. Finally, we set up a portal at http://www.mutarget.com enabling the rapid identification of novel mutational targets. By linking somatic mutations and gene expression, it is possible to identify biomarkers and potential therapeutic targets in different types of solid tumors. The registration-free online platform can increase the speed and reduce the development cost of novel personalized therapies.

Our initial experiences with MR arthrography / Kezdeti tapasztalataink az MR-artrográfiával.

INTRODUCTION: The gold standard method for shoulder surgery imaging is magnetic resonance imaging (MRI). The sensitivity of the conventional MRI for full thickness tears is way above 85%, for partial rotator cuff lesions this number is less than 40%. Diagnostic accuracy is equally low in detecting different variations of anterior labrum lesion and also in injury of the glenohumeral ligaments. Contrast agent given directly into the joint can improve these diagnostic inaccuracies. METHOD: We made the first shoulder joint related MR arthrography in February 2018 at the Semmelweis University. The studied period lasted for 17 months; during that time 29 examinations were performed. For the injection we used gadolinium-based contrast substance. RESULTS: In the case of 26 patients (89.9%), the contrast substance had a good position and distended well. From all of the shoulder MRI examinations, 9 (31%) surgical interventions were made, and 8 surgical findings had the same diagnosis as the radiologic description. CONCLUSION: The contrast substance given into the intraarticular space makes it easier to identify and detect the structures in the joint. The injection under X-ray screening is safe, it is absorbed from the joint in short time, and so far - based on our experience - there has not been any complication. It can help to identify injuries which are difficult to diagnose with conventional MRI, and helps planning before surgery. Orv Hetil. 2020; 161(36): 1514-1521.

Psychological factors affecting Marfan syndrome patients with or without cardiac surgery.

BACKGROUND: Marfan syndrome (MFS) is a systemic connective tissue disorder belonging to a group of rare diseases. Several psychologically distressing factors can challenge life for MFS patients. The aim of the present study was, therefore, to assess the psychological and psychosocial aspects of MFS with the goal of identifying a means of improving disease management for patients. METHODS: A total of 66 adult patients with MFS were enrolled into the study prospectively and were divided into operated (OP) and non-operated (NOP) subgroups. Multiple questionnaire tests were used to determine the mental and physical state of our patients. Demographic and surgical data were collected. The results of the tests were also compared to the Hungarostudy (HS) population (representing the average Hungarian population) by using a propensity-matched control. RESULTS: OP group scores yielded more alcohol consumption (P<0.001), while NOP group showed more sleep disturbances. Scores on the MMSE, BECK, STAI and STAI-T tests showed no significant difference comparing the OP and NOP groups. MFS patients appear to have moderate pain-related disability and mild depressive symptoms and sleep disturbances (P<0.05) compared to the HS group. On 10-point scale, MFS patients were more satisfied with their lives (P<0.001) and considered themselves happier (P<0.001) than the HS population; however, they also spent more days on sick leave and in hospital over the past year. The HS group yielded a higher overall percentage of current smokers and pack-per-year consumption than the MFS patients overall (P=0.003 and P<0.001 respectively). CONCLUSIONS: Marfan patients' psychosocial life differs in many ways (including sleep disturbances, healthier lifestyle, pain-related suffering) from the average Hungarian population. Therefore, as part of a multidisciplinary approach during treatment, modern management of MFS should include psychosocial exploration and psychological support in addition to traditional medical options.

Genomic Mapping Identifies Mutations in RYR2 and AHNAK as Associated with Favorable Outcome in Basal-Like Breast Tumors Expressing PD1/PD-L1.

Treatment with anti-PD-L1 antibodies has shown efficacy in basal-like breast cancer. In this context, identification of pre-activated immune tumors is a main goal. Here we explore mutations in PD1 and PD-L1 high-expressing tumors to identify genomic correlates associated with outcome. To do so, RNA-seq and mutation data from 971 breast cancer patients from the TCGA dataset were used to identify most prevalent mutations in patients with high levels of PD1 and PD-L1. Transcriptomic signatures associated with the selected mutations were identified and analyzed in terms of outcome and immune cell infiltration. We identified co-occurrent mutations in RYR2 and AHNAK in 8% and 5% of basal-like tumors respectively, which conferred good prognosis in patients with high expression of PD1 and PD-L1 genes. The transcriptomic signature associated with these mutations, composed of CXCL9, GBP5, C1QA, IL2RG, CSF2RB, IDO1 and LAG3 genes, also conferred good prognosis and correlated with immune infiltrations within the tumors. The joint signature classified patients with favorable relapse-free survival (HR: 0.28; CI: 0.2-0.38; p = 1.7 × 10-16) and overall survival (HR: 0.18; CI: 0.09-0.34; p = 6.8 × 10-9), showing a stronger prediction capacity than previous reported signatures. In conclusion, we describe two novel mutations and their transcriptomic signature, both associated with a favorable outcome and immune infiltrates in PD1 and PD-L1 high-expressing basal-like tumors.

Perioperative Low Tetraiodothyronine Levels and Adverse Outcomes After Heart Transplantation: A Retrospective, Observational Study.

OBJECTIVES: Thyroid dysfunction has been shown to be associated with increased all-cause mortality and severity of chronic heart failure in critical illness and severe cardiac diseases. The present study was conducted to ascertain the relationship between perioperative free triiodothyronine and free tetraiodothyronine (fT4) levels and postoperative adverse outcomes after heart transplantation (HTX). DESIGN: Retrospective, observational study. SETTING: Single-center study in a quaternary care university clinical center. PARTICIPANTS: The study comprised adult patients who underwent HTX between 2015 and 2019 and had at least 1 perioperative thyroid hormone laboratory test on the day of surgery or in the 24 hours before/after the procedure (free triiodothyronine, fT4, and thyroid-stimulating hormone). INTERVENTIONS: No interventions were applied. MEASUREMENTS AND MAIN RESULTS: The primary outcome was primary graft dysfunction (PGD), defined by the consensus conference of the International Society for Heart and Lung Transplantation. A total of 151 patients were included in the final analyses. Twenty-nine (19.2%) patients had PGD. Fourteen (9.3%) patients had low fT4 levels. An independent association was found between fT4 and PGD (odds ratio 6.49; 95% confidence interval 2.26-18.61; p = 0.001), with adjusted multivariate Cox regression models. CONCLUSION: The perioperative fT4 level could be a prognostic marker of adverse outcomes in HTX. The authors suggest appropriate perioperative monitoring of fT4 levels. Additional research is warranted to examine the optimal timing, dosage, and method of replacement.

Effect of Continuous Epinephrine Infusion on Survival in Critically Ill Patients: A Meta-Analysis of Randomized Trials.

OBJECTIVES: Epinephrine is frequently used as an inotropic and vasopressor agent in critically ill patients requiring hemodynamic support. Data from observational trials suggested that epinephrine use is associated with a worse outcome as compared with other adrenergic and nonadrenergic vasoactive drugs. We performed a systematic review and meta-analysis of randomized controlled trials to investigate the effect of epinephrine administration on outcome of critically ill patients. DATA SOURCES: PubMed, EMBASE, and Cochrane central register were searched by two independent investigators up to March 2019. STUDY SELECTION: Inclusion criteria were: administration of epinephrine as IV continuous infusion, patients admitted to an ICU or undergoing major surgery, and randomized controlled trials. Studies on epinephrine administration as bolus (e.g., during cardiopulmonary resuscitation), were excluded. The primary outcome was mortality at the longest follow-up available. DATA EXTRACTION: Two independent investigators examined and extracted data from eligible trials. DATA SYNTHESIS: A total of 5,249 studies were assessed, with a total of 12 studies (1,227 patients) finally included in the meta-analysis. The majority of the trials were performed in the setting of septic shock, and the most frequent comparator was a combination of norepinephrine plus dobutamine. We found no difference in all-cause mortality at the longest follow-up available (197/579 [34.0%] in the epinephrine group vs 219/648 [33.8%] in the control group; risk ratio = 0.95; 95% CI, 0.82-1.10; p = 0.49; I = 0%). No differences in the need for renal replacement therapy, occurrence rate of myocardial ischemia, occurrence rate of arrhythmias, and length of ICU stay were observed. CONCLUSIONS: Current randomized evidence showed that continuous IV administration of epinephrine as inotropic/vasopressor agent is not associated with a worse outcome in critically ill patients.