Predicting progression of aortic stenosis by measuring serum calcification propensity.

BACKGROUND: The aim of this prospective, double-blinded study in patients with aortic sclerosis was to determine whether a new calcification propensity measure in the serum could predict disease progression. METHODS: We included 129 consecutive patients with aortic sclerosis as assessed during a routine clinical echocardiographic exam. Clinical, echocardiographic, and serum laboratory parameters were collected, including a new blood test providing an overall measure of calcification propensity by monitoring the maturation time of calciprotein particles (T50 test). The echocardiographic exam was repeated after 1 year. Multiple regression analysis was performed to identify independent predictors of the annual increase of peak transvalvular Doppler velocity (∆vmax). Furthermore, the accuracy of the T50 test to detect patients with the most marked stenosis progression was assessed by receiver operating characteristic (ROC)-analysis. RESULTS: Mean age was 75 ± 9 years, 79% were men. The T50 was 271 ± 58 min. Overall, there was no significant stenosis progression between baseline and follow-up (∆vmax 3.8 ± 29.8 cm/s, p = ns). The T50 test was not found to be an independent linear predictor in multivariate testing. By ROC-analysis, however, a T50-value ≤ 242 min was able to significantly detect a ∆vmax above the 90th percentile (∆vmax ≥ 43 cm/s, AUC = 0.67, p = .04, Sensitivity = 69%, Specificity = 70%). CONCLUSIONS: The T50 test showed a modest but significant ability to identify a pronounced aortic stenosis progression in patients with aortic sclerosis. The test could not be established as an independent linear predictor of disease progression, possibly due to the low valvular disease burden and short follow-up interval.

Passive Leg Raise Stress Echocardiography in Severe Paradoxical Low-Flow, Low-Gradient Aortic Stenosis.

BACKGROUND: Dobutamine stress echocardiography is used to increase transvalvular flow in patients with low-flow, low-gradient aortic stenosis (AS). Dobutamine fails to increase the stroke volume index (SVI) in one third of patients. The aim of this study was to test whether passive leg raise (PLR) added to dobutamine could increase SVI and transvalvular flow in patients with severe paradoxical low-flow, low-gradient AS. METHODS: Forty-five patients with apparent severe low-flow, low-gradient AS on the basis of traditional measurements were included. Twenty-five were categorized as belonging to the paradox group (left ventricular ejection fraction [EF] ≥ 50%) and 20 to the low EF group (left ventricular EF < 50% or "classical" low-flow, low-gradient AS) for comparison. A four-step stress echocardiographic examination was performed: resting conditions (rest), PLR alone (PLR), maximal dobutamine infusion rate (Dmax), and a combination of Dmax and PLR (Dmax+PLR). Aortic valve area, SVI, and mean transvalvular flow were calculated using both the velocity-time integral (VTI) of left ventricular outflow tract and the Simpson method. Changes compared with rest and between the stress maneuvers were analyzed. RESULTS: In the paradox group, compared with rest, left ventricular end-diastolic volume was significantly decreased with Dmax but was completely restored with Dmax+PLR (rest vs Dmax vs Dmax+PLR: 61 ± 15 vs 49 ± 18 mL [P < .001] vs 61 ± 18 mL [P = NS]). The smallest increase in SVI in the paradox group was observed during Dmax (PLR vs Dmax vs Dmax+PLR: VTI, 38 ± 4 mL/m2 [P < .001] vs 36 ± 7 mL/m2 [P = .019] vs 41 ± 7 mL/m2 [P < .001]; Simpson, 28 ± 6 mL/m2 [P < .001], 21 ± 7 mL/m2 [P = NS], 27 ± 7 mL/m2 [P = NS]). Compared with Dmax, Dmax+PLR was able to achieve a higher SVI (VTI, 36 ± 7 vs 41 ± 7 mL/m2 [P < .001]; Simpson, 21 ± 7 vs 27 ± 7 mL/m2 [P < .001]) and transvalvular flow with the Simpson method only (179 ± 56 vs 219 ± 56 mL/sec, P < .001), as well as a higher mean gradient (34 ± 10 vs 39 ± 12 mm Hg, P = .003) and AVA with the Simpson method (0.64 ± 0.21 vs 0.73 ± 0.21 cm2, P = .026). In the low EF group, only SVI VTI (31 ± 8 vs 35 ± 7 mL/m2, P = .034) and mean gradient (29 ± 12 vs 34 ± 14 mm Hg, P = .003) were higher with Dmax+PLR. The proportion of patients with SVI VTI ≥ 35 mL/m2 and increases of SVI VTI of >20% compared with rest was highest with Dmax+PLR in both groups. CONCLUSIONS: Dobutamine decreases preload in paradoxical low-flow, low-gradient AS. Adding PLR counteracts this effect, resulting in increased SVI and flow (in one method). The combined stress maneuver allowed reclassification of some patients from severe to moderate AS and may therefore be useful in selected cases in this population in which severity is uncertain.

Treatment for gastrointestinal and pancreatic neuroendocrine tumours: a network meta-analysis.

BACKGROUND: Several available therapies for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials. However, translation of these results into improved care faces several challenges, as a direct comparison of the most pertinent therapies is incomplete. OBJECTIVES: To evaluate the safety and efficacy of therapies for NETs, to guide clinical decision-making, and to provide estimates of relative efficiency of the different treatment options (including placebo) and rank the treatments according to their efficiency based on a network meta-analysis. SEARCH METHODS: We identified studies through systematic searches of the following bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); and Embase from January 1947 to December 2020. In addition, we checked trial registries for ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings. SELECTION CRITERIA: We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic). DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data to a pre-designed data extraction form. Multi-arm studies were included in the network meta-analysis using the R-package netmeta. We separately analysed two different outcomes (disease control and progression-free survival) and two types of NET (gastrointestinal and pancreatic NET) in four network meta-analyses. A frequentist approach was used to compare the efficacy of therapies. MAIN RESULTS: We identified 55 studies in 90 records in the qualitative analysis, reporting 39 primary RCTs and 16 subgroup analyses. We included 22 RCTs, with 4299 participants, that reported disease control and/or progression-free survival in the network meta-analysis. Precision-of-treatment estimates and estimated heterogeneity were limited, although the risk of bias was predominantly low. The network meta-analysis of progression-free survival found nine therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.36 [95% CI, 0.28 to 0.46]), interferon plus somatostatin analogue (HR, 0.34 [95% CI, 0.14 to 0.80]), everolimus plus somatostatin analogue (HR, 0.38 [95% CI, 0.26 to 0.57]), bevacizumab plus somatostatin analogue (HR, 0.36 [95% CI, 0.15 to 0.89]), interferon (HR, 0.41 [95% CI, 0.18 to 0.94]), sunitinib (HR, 0.42 [95% CI, 0.26 to 0.67]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.48 [95% CI, 0.28 to 0.83]), surufatinib (HR, 0.49 [95% CI, 0.32 to 0.76]), and somatostatin analogue (HR, 0.51 [95% CI, 0.34 to 0.77]); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE plus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.26]), everolimus plus somatostatin analogue (HR, 0.12 [95%CI, 0.03 to 0.54]), bevacizumab plus somatostatin analogue (HR, 0.18 [95% CI, 0.04 to 0.94]), interferon plus somatostatin analogue (HR, 0.23 [95% CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [95%CI, 0.12 to 0.88]), and somatostatin analogue (HR, 0.34 [95% CI, 0.16 to 0.76]), with higher efficacy than placebo. Besides everolimus for pancreatic NETs, the results suggested an overall superiority of combination therapies, including somatostatin analogues. The results indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life, but these were reported inconsistently. Evidence from this network meta-analysis (and underlying RCTs) does not support any particular therapy (or combinations of therapies) with respect to patient-centred outcomes (e.g. overall survival and quality of life). AUTHORS' CONCLUSIONS: The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.

Postoperative wound assessment in cattle: How reliable is the back hand palpation?

BACKGROUND: As part of clinical wound assessment in bovine surgery, discrepancies in skin temperature are evaluated by placing the back of the hand on the area to be examined. Generally, an increased skin temperature at the wound site for a prolonged period is considered as an indicator of impaired wound healing. The aim of this study was to verify the reliability of palpation under bovine practice conditions using laparotomy as an example. Fourteen cows (German Holstein) with a left displacement of the abomasum (LDA) without other severe concurrent diseases were examined preoperatively and once daily for ten days after surgery. The skin temperature of the wound site in the right flank was assessed by palpation, followed by thermographic evaluation using an infrared camera after a 45-min acclimatisation period, under standardised conditions in a closed examination room daily for 10 days. RESULTS: All the incisions healed without clinical detectable perturbances. The ambient temperature range during the study period was 7.8 - 24.1 °C. Two groups were retrospectively defined according to the ambient temperature: high ambient temperature (HT group; median: 20.2 °C 25/75 quartile: 18.5 °C / 21.7 °C; n = 6) and low ambient temperature (LT group; 10.8 °C; 9.4 °C / 12.8 °C; n = 8). The temperature differences (Δϑ) between the mean skin temperature of the wound site and a defined reference area cranial to the wound were assessed. A significant negative correlation was found between the ambient temperature (ϑAmb) and Δϑ (r=-0.51; P < 0.001). The Δϑ was postoperatively higher in the cows in the LT group (median of the individual animals 0.8-2.5 °C) than in the HT group (0.1-0.5 °C; P < 0.05). In contrast to the thermographic findings, manual palpation rarely detected local hyperthermia (> 1 °C) at the wound site (sensitivity 0.20; specificity 0.96). CONCLUSIONS: The infrared thermography provides a more reliable assessment of temperature changes at the wound site in comparison to manual palpation. The ambient temperature markedly affects the extent of local hyperthermia at the wound site.

Favourable long-term survival of patients with esophageal cancer treated with extended transhiatal esophagectomy combined with en bloc lymphadenectomy: results from a retrospective observational cohort study.

BACKGROUND: Although considered complex and challenging, esophagectomy remains the best potentially curable treatment option for resectable esophageal and esophagogastric junction (AEG) carcinomas. The optimal surgical approach and technique as well as the extent of lymphadenectomy, particularly regarding quality of life and short- and long-term outcomes, are still a matter of debate. To lower perioperative morbidity, we combined the advantages of a one-cavity approach with extended lymph node dissection (usually achieved by only a two-cavity approach) and developed a modified single-cavity transhiatal approach for esophagectomy. METHODS: The aim of this study was to evaluate the outcome of an extended transhiatal esophageal resection with radical bilateral mediastinal en bloc lymphadenectomy (eTHE). A prospective database of 166 patients with resectable cancers of the esophagus (including adenocarcinomas of the AEG types I and II) were analyzed. Patients were treated between 2001 and 2017 with eTHE at a tertiary care university center. Relevant patient characteristics and outcome parameters were collected and analyzed. The primary endpoint was 5-year overall survival. Secondary outcomes included short-term morbidity, mortality, radicalness of en bloc resection and oncologic efficacy. RESULTS: The overall survival rates at 1, 3 and 5 years were 84, 70, and 61.0%, respectively. The in-hospital mortality rate after eTHE was 1.2%. Complications with a Clavien-Dindo score of III/IV occurred in 31 cases (18.6%). A total of 25 patients (15.1%) had a major pulmonary complication. The median hospital stay was 17 days (interquartile range (IQR) 12). Most patients (n = 144; 86.7%) received neoadjuvant treatment. The median number of lymph nodes resected was 25 (IQR 17). The R0 resection rate was 97%. CONCLUSION: In patients with esophageal cancer, eTHE without thoracotomy resulted in excellent long-term survival, an above average number of resected lymph nodes and an acceptable postoperative morbidity and mortality.

Pulmonary Artery Pressure Ventricularization in a Patient With Carcinoid Heart Disease.

Ventricularization of the pulmonary artery pressure curve is shown, characterized by a steep diastolic pressure fall with mid-diastolic pressure equalization with the right ventricle, which was caused by severe pulmonary valvular regurgitation in a patient with carcinoid heart syndrome. (Level of Difficulty: Beginner.).

Hemodynamic Relevance of Anomalous Coronary Arteries Originating From the Opposite Sinus of Valsalva-In Search of the Evidence.

Coronary artery anomalies (CAA) represent a heterogeneous group of congenital disorders of the arterial coronary circulation, defined by an anomalous origin of the coronary ostium and/or vessel course. Of particular interest are anomalous coronary arteries originating from the opposite sinus of Valsalva (ACAOS). The interarterial variants (with the anomalous vessel situated between the great arteries) are historically called "malignant," based on an anticipated higher risk for myocardial ischemia and sudden cardiac death (SCD), especially affecting young patients during strenuous physical activity. However, the interarterial course itself may not be the predominant cause of ischemia, but rather represents a surrogate for other ischemia-associated anatomical high-risk features. As the exact pathophysiology of ACAOS is not well-understood, there is a lack of evidence-based guidelines addressing optimal diagnostic work-up, downstream testing, sports counseling, and therapeutic options in patients with ACAOS. Therefore, treating physicians are often left with uncertainty regarding the clinical management of affected patients. This review focuses on the pathophysiologic consequences of ACAOS on myocardial ischemia and discusses the concept of the interplay between fixed and dynamic coronary stenosis. Further, we discuss the advantages and limitations of the different diagnostic modalities and give an outlook by highlighting the gaps of knowledge in the assessment of such anomalies.

Immunohistochemical analysis of the expression of cancer-associated fibroblast markers in esophageal cancer with and without neoadjuvant therapy.

Esophageal carcinoma (EC) is one of the most aggressive human malignancies with high rates of resistance to conventional anticancer treatment. Cancer-associated fibroblasts (CAFs) are an important part of the tumor microenvironment and associated with tumor progression. COL11A1, SPARC, and CD90 have been identified as rather specific CAF markers, with COL11A1 expression particularly shown to influence response to chemotherapy. We investigated the impact of CAFs in esophageal cancer with a special focus on response to neoadjuvant treatment (nTX). Two collections of esophageal carcinomas were investigated: 164 cases treated with primary resection and 256 cases receiving nTX before resection. The expression of CAF markers was determined using next-generation tissue microarray (ngTMA®) technology and immunohistochemistry. The presence of COL11A1 and SPARC in fibroblasts within both primary resected cases and nTX-treated cases was associated with unfavorable clinicopathological variables such as higher (y)pT category and lymphatic invasion (p<0.001 each). The presence of COL11A1-positive CAFs was associated with worse overall survival in primary resected cases (HR: 2.162, p = 0.004, CI 95% 1.275-3.686). While in tumors showing regression after nTX, COL11A1-positive CAFs were detected less frequently, SPARC-positive CAFs were enriched after nTX, in both responding and non-responding patients (p < 0.001). Our results support the concept of CAFs as an important factor of tumor promotion and maintenance in EC. The population of CAFs increases with tumor progression and decreases, partly depending on the subtype, after regression following nTX. CAFs may serve as potential target for future therapeutic approaches for these highly aggressive tumors.

Coronary wave intensity patterns in stable coronary artery disease: influence of stenosis severity and collateral circulation.

Objective: Wave intensity analysis is a method that allows separating pulse waves into components generated proximally and in the periphery of arterial trees, as well as characterising them as accelerating or decelerating. The early diastolic suction wave (eaDSW) is one of the most prominent wave events in the coronaries. The aim of this study was to determine whether (1) microvascular dilatation directly influences its energy, (2) stenosis severity can be assessed proximal to stenoses, (3) distal pulse wave entrapment exists in the presence of stenoses and (4) coronary collaterals influence wave entrapment. Methods: In 43 coronary artery disease patients, Doppler flow velocity and pressure measurements were performed in a proximal coronary segment at rest, in a distal segment at rest, during adenosine-induced hyperaemia and during balloon occlusion. Wave energies were calculated as the area under the wave intensity curves. Results: The eaDSW energy showed a significant increase during hyperaemia, but did not differ between proximal and distal segments. There was no significant correlation between eaDSW energy and coronary stenosis severity. Pulse wave entrapment could not be observed consistently in the distal segments. Consequently, the effect of coronary collaterals on pulse wave entrapment could not be studied. Conclusions: Microvascular dilation in the coronary circulation increases distal eaDSW energy. However, it does not show any diagnostically useful variation between measurement sites, various stenosis degrees and amount of collateral flow. The assessment eaDSW and its reflections were not useful for the quantification of coronary stenosis severity or the collateral circulation in clinical practice.

Correction: A specific expression profile of LC3B and p62 is associated with nonresponse to neoadjuvant chemotherapy in esophageal adenocarcinomas.

[This corrects the article DOI: 10.1371/journal.pone.0197610.].

Association of Surgical Volume and Quality Management in Thyroid Surgery: A Two-Nation Multicenter Study.

BACKGROUND: High-volume caseload in thyroid surgery is associated with lower postoperative complication rates resulting to better outcomes. The aim of the present study was to investigate the correlation of the departments' annual number of thyroid surgeries on the adherence to consensus guidelines and on the implementation of measures for quality assurance. METHODS: In 2016, we sent an anonymous electronic survey with questions related to the perioperative management in thyroid surgery to all directors of departments in operative medicine in Switzerland and Austria. We compared the pre- and postoperative management with the summarized recommendations of the four most frequently used consensus guidelines. Analogously, we analyzed the implementation of six measures for quality assurance related to thyroid surgery for each participating department. Using logistic regression analysis, we evaluated the correlation of number of guidelines respected and number of measures for quality assurance with the departments' annual number of surgeries performed. Furthermore, we evaluated the number of departments providing thyroid cancer surgery and their experience in neck dissection. RESULTS: The management corresponded in 64.0% to the summarized recommendations. Adherence to the summarized recommendations and implementation of measures for quality assurance were significantly more likely with increasing numbers of surgeries performed (p = 0.049 and p < 0.001). Ninety-two departments provided thyroid cancer surgery, whereas 12/92 (13.0%) were not able to perform central and/or lateral neck dissection. CONCLUSION: Consensus guidelines are insufficiently implemented within thyroid surgery, and quality management is associated with surgical volume.

Therapeutic Options for Neuroendocrine Tumors: A Systematic Review and Network Meta-analysis.

IMPORTANCE: Multiple therapies are currently available for patients with neuroendocrine tumors (NETs), yet many therapies have not been compared head-to-head within randomized clinical trials (RCTs). OBJECTIVE: To assess the relative safety and efficacy of therapies for NETs. DATA SOURCES: PubMed, Embase, the Cochrane Central Register of Controlled Trials, trial registries, meeting abstracts, and reference lists from January 1, 1947, to March 2, 2018, were searched. Key search terms included neuroendocrine tumors, gastrointestinal neoplasms, therapy, and randomized controlled trial. STUDY SELECTION: Randomized clinical trials comparing 2 or more therapies in patients with NETs (primarily gastrointestinal and pancreatic) were evaluated. Thirty RCTs met the selection criteria. DATA EXTRACTION AND SYNTHESIS: Pairs of independent reviewers screened studies, extracted data, and assessed the risk of bias. A network meta-analysis with a frequentist approach was used to compare the efficacy of therapies; the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. MAIN OUTCOMES AND MEASURES: Disease control, progression-free survival, overall survival, adverse events, and quality of life. RESULTS: The systematic review identified 30 relevant RCTs comprising 3895 patients (48.4% women) assigned to 22 different therapies for NETs. These therapies showed a broad range of risk for serious and nonserious adverse events. The network meta-analyses included 16 RCTs with predominantly a low risk of bias; nevertheless, precision-of-treatment estimates and estimated heterogeneity were limited. The network meta-analysis found 7 therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.35 [95% CI, 0.28-0.45]), everolimus plus somatostatin analogue (HR, 0.35 [95% CI, 0.25-0.51]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.44 [95% CI, 0.26-0.75]), interferon (HR, 0.37 [95% CI, 0.16-0.83]), interferon plus somatostatin analogue (HR, 0.31 [95% CI, 0.13-0.71]), somatostatin analogue (HR, 0.46 [95% CI, 0.33-0.66]), and sunitinib (HR, 0.42 [95% CI, 0.26-0.67]), and 5 therapies for gastrointestinal NETs: bevacizumab plus somatostatin analogue (HR, 0.22 [95% CI, 0.05-0.99]), everolimus plus somatostatin analogue (HR, 0.31 [95% CI, 0.11-0.90]), interferon plus somatostatin analogue (HR, 0.27 [95% CI, 0.07-0.96]), Lu 177-dotatate plus somatostatin analogue (HR, 0.08 [95% CI, 0.03-0.26], and somatostatin analogues (HR, 0.40 [95% CI, 0.21-0.78]) with higher efficacy than placebo and suggests an overall superiority of combination therapies. CONCLUSIONS AND RELEVANCE: The findings from this study suggest that a range of efficient therapies with different safety profiles is available for patients with NETs.

Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells.

Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort (n = 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients.

A specific expression profile of LC3B and p62 is associated with nonresponse to neoadjuvant chemotherapy in esophageal adenocarcinomas.

Paclitaxel is a powerful chemotherapeutic drug, used for the treatment of many cancer types, including esophageal adenocarcinomas (EAC). Autophagy is a lysosome-dependent degradation process maintaining cellular homeostasis. Defective autophagy has been implicated in cancer biology and therapy resistance. We aimed to assess the impact of autophagy on chemotherapy response in EAC, with a special focus on paclitaxel. Responsiveness of EAC cell lines, OE19, FLO-1, OE33 and SK-GT-4, to paclitaxel was assessed using Alamar Blue assays. Autophagic flux upon paclitaxel treatment in vitro was assessed by immunoblotting of LC3B-II and quantitative assessment of WIP1 mRNA. Immunohistochemistry for the autophagy markers LC3B and p62 was applied on tumor tissue from 149 EAC patients treated with neoadjuvant chemotherapy, including pre- and post-therapeutic samples (62 matched pairs). Tumor response was assessed by histology. For comparison, previously published data on 114 primary resected EAC cases were used. EAC cell lines displayed differing responsiveness to paclitaxel treatment; however this was not associated with differential autophagy regulation. High p62 cytoplasmic expression on its own (p ≤ 0.001), or in combination with low LC3B (p = 0.034), was associated with nonresponse to chemotherapy, regardless of whether or not the regiments contained paclitaxel, but there was no independent prognostic value of LC3B or p62 expression patterns for EAC after neoadjuvant treatment. p62 and related pathways, most likely other than autophagy, play a role in chemotherapeutic response in EAC in a clinical setting. Therefore p62 could be a novel therapeutic target to overcome chemoresistance in EAC.

Frequency, Reasons, and Impact of Premature Ticagrelor Discontinuation in Patients Undergoing Coronary Revascularization in Routine Clinical Practice: Results From the Bern Percutaneous Coronary Intervention Registry.

BACKGROUND: Although ticagrelor has improved clinical outcomes among patients with acute coronary syndrome compared with clopidogrel, adherence to this new antiplatelet agent in real-world practice has not been fully investigated. METHODS AND RESULTS: Between November 2011 and June 2014, 1278 of 4831 consecutive patients (26.5%) undergoing percutaneous coronary intervention at a tertiary care center were treated with ticagrelor. Premature ticagrelor cessation was categorized into (1) change, when ticagrelor was replaced by prasugrel; (2) de-escalation, when ticagrelor was replaced by clopidogrel; and (3) premature discontinuation, when ticagrelor was discontinued without P2Y12 inhibitor replacement. Of 1278 patients treated with ticagrelor, premature treatment cessation occurred in 212 patients (17%). De-escalation to clopidogrel was the most frequent scenario (57%; n=120), followed by premature discontinuation (28%; n=60) and change to prasugrel (15%; n=32). Reasons for ticagrelor cessation included adverse effects (49%), initiation of oral anticoagulation (19%), and unspecified general practitioner preference (10%). Most frequent adverse effects leading to premature ticagrelor cessation were bleeding (41%), dyspnea (29%), and gastrointestinal symptoms (18%). Premature ticagrelor cessation was not associated with an increased risk of cardiac death, myocardial infarction, or stroke (hazard ratio, 0.73; 95% confidence interval: 0.40-1.32; P=0.29). CONCLUSIONS: Premature ticagrelor cessation in routine clinical practice occurred in 1 of 6 patients and was primarily related to adverse effects among which bleeding and dyspnea were the most frequent. Although premature ticagrelor cessation was not associated with adverse cardiovascular outcomes, this finding requires careful interpretation in view of the modest sample size. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02241291.

Left ventricular afterload reduction by transcatheter aortic valve implantation in severe aortic stenosis and its prompt effects on comprehensive coronary haemodynamics.

AIMS: In this study we aimed to test the hypothesis that left ventricular (LV) afterload reduction in severe aortic valve stenosis (AS) by transcatheter aortic valve implantation (TAVI) acutely improves coronary haemodynamics. METHODS AND RESULTS: This was a prospective, pathophysiologic study in 40 patients with severe AS undergoing TAVI. Endpoints were determined invasively immediately before and after TAVI without altering coronary stenotic lesions if present. Myocardial hyperaemia was induced by intravenous adenosine. The primary study endpoints were coronary flow reserve (thermodilution-derived CFR), and fractional flow reserve (FFR). The secondary study endpoint was coronary collateral flow index (CFI) as obtained during a one-minute coronary balloon occlusion. CFR was 1.9±0.9 before TAVI and 2.0±1.0 after TAVI (p=0.72). FFR was 0.90±0.08 before TAVI and 0.93±0.08 after TAVI (p=0.0021). The TAVI-induced increase in FFR was related to a significant decrease in hyperaemic mean aortic pressure from 71±16 mmHg before TAVI to 67±15 mmHg after TAVI (p=0.0099). Hyperaemic CFI increased from 0.127±0.083 before to 0.146±0.090 after TAVI (p=0.0508). CONCLUSIONS: CFR appears not to be acutely affected by LV afterload reduction among patients with severe AS in response to TAVI. However, it acutely improves FFR; this occurs via lowering of mean aortic pressure. Hyperaemic coronary collateral flow index tends to augment in response to TAVI.

Application of the 8th edition of the AJCC yTNM staging system shows improved prognostication in a single center cohort of esophageal carcinomas.

BACKGROUND: The 8th edition of the AJCC TNM staging system presents for the first time a specific classification for esophageal carcinomas treated with neoadjuvant therapy (yTNM8). In this single center study, we applied the novel staging system in a "real life" case series and compared the prognostic value of yTNM8 with the preceding 7th edition (TNM7). METHODS: Out of 272 consecutive esophageal carcinomas that were treated during a 15-year period in one surgical center, all 198 cases that had undergone neoadjuvant therapy were reviewed and classified according to TNM7 and yTNM8. RESULTS: 50 ypT0 cases that had no specific staging in TNM7 were included into stages I (ypT0N0M0; n = 42), IIIA (ypT0N1M0; n = 6), IVA (ypT0N3M0; n = 1) and IVB (ypT0N0M1; n = 1) in yTNM8. Both systems showed significant prognostic impact (p < 0.0001 each). yTNM8 was superior regarding prognostication with lower values for goodness-of-fit criteria (Akaike Information Criterion 1589.331 vs 1593.239; and Schwarz Bayesian Criterion 1605.487 vs.1619.088). However, in TNM7, stage IIB tumors had better prognosis than stage IIA tumors, and likewise, stage IIIA tumors better compared to stage II in yTNM8. CONCLUSIONS: yTNM8 allows accurate staging of esophageal carcinomas treated by neoadjuvant therapy, with slightly improved prognostication compared to TNM7. Additional data acquisition will be necessary for further improvement of staging for esophageal carcinomas after neoadjuvant treatment.

Osteointegration of Porous Poly-ε-Caprolactone-Coated and Previtalised Magnesium Implants in Critically Sized Calvarial Bone Defects in the Mouse Model.

Metallic biomaterials are widely used in maxillofacial surgery. While titanium is presumed to be the gold standard, magnesium-based implants are a current topic of interest and investigation due to their biocompatible, osteoconductive and degradable properties. This study investigates the effects of poly-ε-caprolactone-coated and previtalised magnesium implants on osteointegration within murine calvarial bone defects: After setting a 3 mm × 3 mm defect into the calvaria of 40 BALB/c mice the animals were treated with poly-ε-caprolactone-coated porous magnesium implants (without previtalisation or previtalised with either osteoblasts or adipose derived mesenchymal stem cells), porous Ti6Al4V implants or without any implant. To evaluate bone formation and implant degradation, micro-computertomographic scans were performed at day 0, 28, 56 and 84 after surgery. Additionally, histological thin sections were prepared and evaluated histomorphometrically. The outcomes revealed no significant differences within the differently treated groups regarding bone formation and the amount of osteoid. While the implant degradation resulted in implant shifting, both implant geometry and previtalisation appeared to have positive effects on vascularisation. Although adjustments in degradation behaviour and implant fixation are indicated, this study still considers magnesium as a promising alternative to titanium-based implants in maxillofacial surgery in future.

Quantification of Multiple Mitral Regurgitant Jets: An In Vitro Validation Study Comparing Two- and Three-Dimensional Proximal Isovelocity Surface Area Methods.

BACKGROUND: The accuracy of the proximal isovelocity surface area (PISA) method for the quantification of mitral regurgitation (MR), in the case of multiple jets, is unknown. The aim of this study was to evaluate different two-dimensional (2D) and three-dimensional (3D) PISA methods using 3D color Doppler data sets. METHODS: Several regurgitant volumes (Rvols) were simulated using a pulsatile pump connected to a phantom equipped with single and double regurgitant orifices of different sizes and interspaces. A flowmeter served as the reference method. Transthoracic (TTE) and transoesophageal echocardiography (TEE) were used to acquire the 3D data sets. Offline, Rvols were calculated by 2D PISA methods based on hemispheric and hemicylindric assumptions and by 3D integrated PISA. RESULTS: A fusion of the PISA was observed in the setting of narrow-spaced regurgitant orifices; compared with flowmeter, Rvol was underestimated using the single hemispheric PISA model (TTE: Bland-Altman bias ± limit of agreement, -17.5 ± 8.9 mL; TEE: -15.9 ± 7.3 mL) and overestimated using the double hemispheric PISA model (TTE: +7.1 ± 14.6 mL; TEE: +10.4 ± 11.9 mL). The combined approach (hemisphere for single orifice, hemicylinder with two bases for nonfused PISAs, and hemicylinder with one base for fused PISAs) was more precise (TTE: -3.4 ± 6.3 mL; TEE: -1.9 ± 5.6 mL). Three-dimensional integrated PISA was the most accurate method to quantify Rvol (TTE: -2.1 ± 6.5 mL; TEE -3.2 ± 4.8 mL). CONCLUSIONS: In the setting of double MR orifices, the 2D combined approach and integrated 3D PISA appear to be superior as compared with the conventional hemispheric method, thus providing tools for the challenging quantification of MR with multiple jets.