Perioperative and Long-Term Outcomes in Patients Undergoing Synchronous Carotid Endarterectomy and Coronary Artery Bypass Grafting: A Single-Center Experience.

INTRODUCTION: Patients requiring coronary artery bypass grafting (CABG) and carotid endarterectomy (CEA) can be managed with staged (CEA before CABG), reverse staged (CABG before CEA) or synchronous treatment. This single-center retrospective study evaluated the outcomes in patients undergoing planned synchronous CEA and CABG. METHODS: Between 2000 and 2020 a total of 185 patients with symptomatic triple-vessel or left main coronary artery disease associated with 70-99% asymptomatic or 50-99% symptomatic uni- or bilateral internal carotid artery (ICA) stenosis underwent synchronous CEA and CABG at our institution. Study endpoints were defined as mortality, stroke and myocardial infarction at 30 days. Additionally, the composite endpoint of these events was investigated. RESULTS: At 30 days, mortality, stroke and myocardial infarction rates were 5.9%, 8.1% (permanent [unresolved deficit at discharge] 5.4%) and 3.8%, respectively, and the composite endpoint was reached in 13.0% of patients. Patients suffering from a stroke more frequently had a contralateral 70-99% ICA stenosis (60.0% vs. 17.3%; p < 0.001), peripheral artery disease (73.3% vs. 38.9%; p = 0.013) and prolonged cardiopulmonary bypass time (mean 119 ± 62 min vs. 84 ± 29 min; p = 0.012). Multivariate logistic regression analysis revealed the duration of cardiopulmonary bypass (odds ratio [OR] 1.024; 95% confidence interval [CI] 1.002-1.046; p = 0.034), a history of type 2 diabetes mellitus (OR 5.097; 95% CI 1.161-22.367; p = 0.031) and peripheral artery disease (OR 5.814; 95% CI 1.231-27.457; p = 0.026) as independent risk factors for reaching the composite endpoint. CONCLUSION: Patients undergoing synchronous CEA and CABG face an elevated risk of perioperative cardiovascular events, particularly an increased stroke risk in patients with symptomatic and bilateral ICA stenosis. Graphical Abstract available for this article.

Establishment of the deuterium oxide dilution method as a new possibility for determining the transendothelial water permeability.

Increase in transendothelial water permeability is an essential etiological factor in a variety of diseases like edema and shock. Despite the high clinical relevance, there has been no precise method to detect transendothelial water flow until now. The deuterium oxide (D2O) dilution method, already established for measuring transepithelial water transport, was used to precisely determine the transendothelial water permeability. It detected appropriate transendothelial water flow induced by different hydrostatic forces. This was shown in four different endothelial cell types. The general experimental setup was verified by gravimetry and absorbance spectroscopy. Determination of transendothelial electrical resistance (TEER) and immunocytochemical staining for proteins of the cell-cell contacts were performed to ensure that no damage to the endothelium occurred because of the measurements. Furthermore, endothelial barrier function was modulated. Measurement of transendothelial water flux was verified by measuring the TEER, the apparent permeability coefficient and the electrical capacity. The barrier-promoting substances cyclic adenosine monophosphate and iloprost reduced TEER and electrical capacity and increased permeability. This was accompanied by a reduced transendothelial water flux. In contrast, the barrier-damaging substances thrombin, histamine and bradykinin reduced TEER and electrical capacity, but increased permeability. Here, an increased water flow was shown. This newly established in vitro method for direct measurement of transendothelial water permeability was verified as a highly precise technique in various assays. The use of patient-specific endothelial cells enables individualized precision medicine in the context of basic edema research, for example regarding the development of barrier-protective pharmaceuticals.

Open Heart Surgery in Jehovah's Witnesses: A Propensity Score Analysis.

BACKGROUND: Jehovah's Witnesses (JW) refuse allogeneic blood transfusions and therefore pose a unique challenge in case of major surgery. This retrospective study reviewed an experience with JW patients who were undergoing open heart surgery. METHODS: By using patient blood management strategies, 35 adult JW patients underwent cardiac surgery at Kepler University Hospital in Linz, Austria between 2008 and 2017. Outcomes were compared with patients who accepted blood transfusions (non-JW patients) by using propensity score matching. RESULTS: There were no significant differences in clinical and operative data between the groups. Twelve JW patients (34.3%) were pretreated with erythropoietin and iron, with a preoperative increase in mean hemoglobin of 2.0 g/dL. On admission, hemoglobin was 14.1 ± 1.1 g/dL in JW patients, compared with 13.2 ± 2.0 g/dL in non-JW patients (P = .022). The hematocrit in JW patients was higher throughout the hospital stay, even though 51.4% of non-JW patients received allogeneic red blood cell transfusions. The perioperative red blood cell loss was significantly lower in JW patients than in non-JW patients (619 ± 420 mL vs 929 ± 520 mL; P = .010). Major complication rates were not different between the groups. The hemoglobin at discharge was 11.5 ± 1.5 g/dL in JW patients compared with 10.3 ± 1.3 g/dL in non-JW patients (P < .001). In-hospital mortality was 2.9% in each group, and long-term survival was comparable. CONCLUSIONS: By implementing patient blood management, open heart surgery in JW patients can be performed with low morbidity and mortality. Preoperative optimization of hemoglobin and minimization of perioperative blood loss are cornerstones in the prevention of blood loss, anemia, and transfusions.

External Prosthetic Reinforcement of the Pulmonary Autograft.

BACKGROUND: Neo-aortic root dilatation accounts for the majority of reoperations needed after the Ross procedure with implantation of the pulmonary autograft as complete root replacement. This study evaluates early results of external prosthetic reinforcement of the autograft. METHODS: From July 2015 to October 2017, 16 adolescent and adult patients received a Ross procedure at our department by this technique. A congenital-dysplastic valve was present in 13 patients, including 9 patients with a bicuspid aortic valve. Clinical and echocardiographic follow-up is complete with a mean duration of 19.7 ± 5.8 months. RESULTS: The mean age at operation was 27.1 ± 16.1 years. Mean aortic cross-clamping time was 102 ± 39 minutes. No bleeding complication occurred. The median stay on the intensive care unit was 2 days. In-hospital mortality was 0%. All patients were discharged with no or trivial aortic regurgitation. In one patient both the autograft and homograft were replaced because of endocarditis 3 months after the primary operation, leading to 93.8% freedom from reoperation at 2 years. There were no late deaths during the study period. The latest echocardiography confirmed absence of aortic regurgitation grade >I in all patients. Neo-aortic root diameters remained stable during follow-up. CONCLUSION: The presented modification of the Ross procedure does not prolong ischemia time, and can be performed with a low operative morbidity and mortality and an excellent early valve function.

Giant cell arteritis as unusual cause of critical arm ischemia.

Giant cell arteritis is an inflammatory vasculopathy of unknown etiology that typically affects the carotid artery and its branches. Symptomatic involvement of upper extremity arteries is uncommon. We report a case of a 70-year-old woman with polymyalgia rheumatica who presented with critical arm ischemia, constitutional symptoms, and elevated erythrocyte sedimentation rate. Urgent revascularization by a carotid-brachial artery bypass was performed. Histopathologic evaluation of a specimen obtained intraoperatively from the occluded axillary artery confirmed the diagnosis, and corticosteroid therapy was initiated. Large-vessel vasculitis should be considered a rare differential diagnosis in occlusive disease of the upper extremity.

Femoral Artery Aneurysm Repair in a Patient With a Fibrillin-2 Mutation.

Degenerative femoral artery aneurysms are uncommon and often associated with aneurysm in other distributions. We report a case of a 68-year-old man with multianeurysmal disease involving the aorta, iliac, femoral, and popliteal arteries managed interdisciplinary by stent-graft placement and open surgical repair. Genetic testing revealed a variant in the FBN2 gene encoding fibrillin-2, an important component of microfibrils. We detail arterial reconstruction of the femoral artery and discuss incidence, diagnosis, and therapy of femoral artery aneurysms.

Pseudoaneurysm of the Radial Artery After a Bicycle Fall.

We report a case of a 64-year-old man who developed a painful pulsatile mass in the distal forearm after a bicycle fall with fracture of the wrist. Ultrasonography confirmed a 2.5-cm large pseudoaneurysm of the radial artery. The patient underwent surgical exploration. The pseudoaneurysm was resected and the defect in the arterial wall was reconstructed with an autologous saphenous vein patch. We suggest that the double arterial supply of the hand should be preserved whenever possible.

Valve-sparing root replacement for freestanding pulmonary autograft aneurysm after the Ross procedure.

OBJECTIVE: Autograft dilatation is the main long-term complication following the Ross procedure using the freestanding root replacement technique. We reviewed our 25-year experience with the Ross procedure with a special emphasis on valve-sparing reoperations. METHODS: From 1991 to 2016, 153 patients (29.6 ± 16.6 years; 29.4% pediatric) underwent a Ross operation at our institution with implantation of the autograft as freestanding root replacement. The follow-up is 98.7% complete with a mean of 12.2 ± 5.5 years. RESULTS: Mortality at 30-days was 2.0%. Echocardiography documented no or trivial aortic regurgitation in 99.3% of the patients at discharge. Survival probability at 20 years was 85.4%. No case of autograft endocarditis occurred. Autograft deterioration rate was 2.01% per patient-year, and freedom from autograft reoperation was 75.3% at 15 years. A reoperation for autograft aneurysm was required in 35 patients (22.9%) at a mean interval of 11.1 ± 4.6 years after the Ross procedure. A valve-sparing root replacement was performed in 77% of patients, including 10 David and 17 Yacoub procedures with no early mortality. Three patients required prosthetic valve replacement within 2 years after a Yacoub operation. At latest follow-up, 92% of all surviving patients still carry the pulmonary autograft valve. Freedom from autograft valve replacement was 92.1% at 15 years. CONCLUSIONS: Using the David or Yacoub techniques, the autograft valve can be preserved in the majority of patients with root aneurysms after the Ross procedure. Reoperations can be performed with no early mortality, a good functional midterm result, and an acceptable reintervention rate.

Long-term Evaluation of the Ross Procedure in Acute Infective Endocarditis.

Optimal valve substitute for young patients with aortic valve endocarditis remains controversial. Given its better resistance to infection, the Ross procedure is an attractive alternative to prosthetic valve replacement or homograft implantation. The objective of this study was to assess long-term outcomes of the Ross procedure in this indication. From January 1991 to April 2017, 190 patients underwent a Ross procedure at our institution. Acute endocarditis was the indication for operation in 19 patients, including 6 patients with a bicuspid aortic valve. The pulmonary autograft was implanted as freestanding root replacement in all patients. The clinical follow-up is 100% complete, with a mean of 12.0 ± 5.7 years. The mean age of the study population was 35.9 ± 11.5 years. Moderate or severe aortic regurgitation was present in 84.2% of the patients. Systemic embolization had occurred in 36.8% of the patients. The mean aortic cross-clamp time was 126 ± 24 minutes. The median length of stay on the intensive care unit was 1 day. Mortality at 30 days was 5.3% (1 patient with gastrointestinal bleeding). Echocardiography at hospital discharge documented no or trivial aortic regurgitation in all patients. No case of recurrent endocarditis affecting the autograft occurred. One patient (0.4% per patient-year) was reoperated 1.8 years after the Ross procedure for homograft endocarditis. Three patients (15.8%) were reoperated for autograft aneurysm. The Ross procedure is a safe and effective alternative to prosthetic valve replacement or homograft implantation in selected young patients with acute endocarditis with a low rate of recurrent infection.

Comparison of a prototype reverse hybridization assay and MethyLight for detection of SFRP2 promotor methylation in fecal DNA.

BACKGROUND: This study aimed to evaluate the diagnostic performance of a novel nonquantitative methylation-specific reverse hybridization (MSRH) assay to detect secreted frizzled-related protein 2 (SFRP2) promotor methylation in fecal DNA. METHODS: SFRP2 promoter methylation was investigated in stool DNA isolated from 18 colorectal cancer (CRC) patients and 22 healthy controls using the MSRH assay based on methylation-specific DNA amplification followed by reverse hybridization of biotinylated amplicons to sequence-specific methylation detection probes, with MethyLight serving as a reference method. RESULTS: SFRP2 promotor methylation as determined by MSRH vs. MethyLight showed a sensitivity and specificity of 61.1% and 86.3% vs. 77.7% and 77.3%, respectively. Moderate agreement (ĸ = 0.54, 95% confidence interval [95% CI], 0.29-0.80, p<0.001) was observed between the 2 methods. However, the differences in SFRP2 promotor methylation observed between CRC patients and healthy individuals by both assays were statistically significant (p<0.001). CONCLUSIONS: Our findings, although limited by the small sample size, do not support the use of the MSRH assay for CRC screening in stool.

Biological Subtypes of Triple-Negative Breast Cancer.

Triple-negative breast cancers (TNBCs) are defined as tumors that are negative for estrogen, progesterone and HER-2 receptor. At a percentage of 10-20% TNBCs represent a minority in all breast cancers. However, because of the poor prognosis this particular subtype, triple negative disease accounts for a disproportionate number of metastatic cases and breast cancer deaths. Identification of its subtypes is essential for understanding the biological characteristics and clinical behavior of TNBC, as well as for developing personalized treatments. This review will focus on the great progress that has been made in the past few years on identifying new targets in TNBC subtypes and a variety of new treatment options that are on the verge of routine clinical application.

14-3-3 sigma and p53 expression in gastric cancer and its clinical applications.

14-3-3 sigma (σ) induces G2 arrest enabling the repair of damaged DNA. The function of 14-3-3 σ is frequently lost in tumor cells, indicating a potential tumor suppressor function. The purpose of this study was to evaluate the prognostic value of 14-3-3 σ expression in human gastric cancer. 14-3-3 σ expression was analyzed by immunohistochemistry in 157 tumor samples of patients, who underwent resection for gastric cancer. Since 14-3-3 σ is involved in the p53 network, p53 expression was detected in parallel and correlated with 14-3-3 σ. 14-3-3 σ was found to be overexpressed in 75 (47.8%) of 157 cases, the overexpression rate of p53 protein was 27.4%. 14-3-3 σ overexpression was statistically significantly associated with pT-stage (p=0.041) pN-stage (p=0.015) and UICC-stage (p=0.019) and showed a borderline significance with Lauren classification (p=0.057). Univariate survival calculations revealed a coexistent 14-3-3 σ and p53 overexpression as a significant predictor of disease-free survival. Multivariate analysis did not unfold 14-3-3 as an independent prognostic factor for disease-free survival and overall survival. Concomitant 14-3-3 σ and p53 overexpression in tumor cells of patients with gastric cancer identifies a population of patients with relatively unfavorable prognosis.

Circulating cell-free DNA in plasma of locally advanced rectal cancer patients undergoing preoperative chemoradiation: a potential diagnostic tool for therapy monitoring.

Circulating cell-free DNA opens up an interesting field for therapy monitoring, in particular during multimodal therapy protocols. The objective of this proof of principle study was to evaluate whether the amount of circulating plasma DNA has the potential to serve as a marker for therapy monitoring during the treatment course of locally advanced rectal cancer patients. We especially focused on kinetics of circulating DNA to assess whether variances in kinetics have the potential to discriminate between therapy responders and nonresponders. The amount of circulating DNA in plasma of rectal cancer patients undergoing preoperative chemoradiation was determined using real-time PCR before chemoradiation, after the end of chemoradiation and at the end of treatment. The study population was divided into responders (ypT0-T2 stage) and nonresponders (ypT3-T4 stage). Both groups showed comparable median plasma DNA values before and after the end of chemoradiation. At the end of treatment responders showed a further decrease in circulating DNA, whereas in nonresponders the circulating DNA manifestly increased (P = 0.006). This study demonstrates that circulating DNA in plasma of rectal cancer patients undergoing preoperative chemoradiation might serve as a surrogate marker to discriminate between responders and nonresponders. Therefore, we hypothesize that quantification of plasma DNA could be of use as an easily accessible tool for therapy monitoring in these patients.

Dickkopf-3 as a new potential marker for neoangiogenesis in colorectal cancer: expression in cancer tissue and adjacent non-cancerous tissue.

Gene expression of Dickkopf-3 (Dkk-3) has been shown to be upregulated in tumor endothelium of colorectal cancer (CRC). For the first time, we analyzed Dkk-3 protein expression in CRC and its potential as a marker for neoangiogenesis. We used tissue microarrays (TMAs) to investigate Dkk-3 in microvessels of 403 CRC samples, 318 appropriate adjacent non-cancerous samples and 127 normal colorectal samples. Of cancer samples with CD31-positive microvessels, 67.7% were positive for Dkk-3. Dkk-3 staining was demonstrated in endothelial cells of all microvessels in nearly all cases. Dkk-3-positive samples showed a higher mean microvessel count than did Dkk-3-negative samples (P=0.001). Dkk-3 expression increased with rising numbers of microvessels per sample (P<0.0001). In adjacent samples with CD31-positive microvessels, 56% were Dkk-3-positive in all microvessels. Similar to cancer samples, Dkk-3-positive adjacent samples had a higher mean microvessel count than did Dkk-3-negative samples (P<0.0001), and Dkk-3 expression also increased with rising numbers of microvessels (P<0.0001). All microvessels in normal mucosa samples were negative for Dkk-3. Dkk-3 can be considered a putative pro-angiogenic protein in neovascularization and may possibly be a marker for neoangiogenesis in CRC. Further investigations will elucidate whether Dkk-3 is a target structure for novel therapies.

SFRP2 methylation in fecal DNA--a marker for colorectal polyps.

INTRODUCTION: DNA methylation of secreted frizzled-related proteins (SFRPs) can be detected in colorectal cancer (CRC) tissue, in tissue of adenomas, and in aberrant crypt foci, whereas in normal colorectal mucosa tissue, SFRP genes are unmethylated. Recently, our study group was able to demonstrate SFRP2 methylation as the most sensitive single DNA-based marker in stool for identification of CRC. The purpose of this study was to clarify whether SFRP2 methylation in fecal DNA can be found in stool of individuals with hyperplastic and adenomatous colorectal polyps. MATERIALS AND METHODS: Patients who were diagnosed with colorectal polyps or showed negative colonoscopy were included in this study. DNA from stool samples was isolated. SFRP2 methylation was assessed by means of MethyLight. RESULTS: Stool samples from 68 individuals were checked for DNA content; 23% of the samples (6 of 26) from healthy controls, 46% of the samples (6 of 13) from patients with hyperplastic polyps, and 45% of the samples (13 of 29) from patients with adenomas were positive for human DNA. SFRP2 methylation in stool samples was found in none of the healthy controls, in 33% (2 of 6) patients with hyperplastic polyps, and in 46% (6 of 13) patients with adenomas. Statistical analysis revealed that the frequency of SFRP2 methylation increased significantly (P=0.028) from healthy controls to patients with hyperplastic polyps and to patients with adenomas. CONCLUSIONS: In the current study, we report for the first time that SFRP2 methylation in fecal DNA increases significantly from healthy controls to patients with hyperplastic polyps and to patients with adenomas. SFRP2 methylation may serve as a marker for molecular stool-based adenoma and CRC screening.

DNA methylation in colorectal cancer--impact on screening and therapy monitoring modalities?

Colorectal cancer (CRC) is a common malignancy. It arises from benign neoplasms and evolves into adenocarcinomas through a stepwise histological progression sequence, proceeding from either adenomas or hyperplastic polyps/serrated adenomas. Genetic alterations have been associated with specific steps in this adenoma-carcinoma sequence and are believed to drive the histological progression of CRC. Recently, epigenetic alterations (especially DNA methylation) have been shown to occur in colon polyps and CRC. The aberrant methylation of genes appears to act together with genetic alterations to drive the initiation and progression of colon polyps to CRC. DNA methylation changes have been recognized as one of the most common molecular alterations in human tumors, including CRC. Because of the ubiquity of DNA methylation changes and the ability to detect methylated DNA in several body fluids (blood, stool), this specifically altered DNA may serve, on the one hand, as a possible new screening marker for CRC and, on the other hand, as a tool for therapy monitoring in patients having had neoplastic disease of the colorectum. As many CRC patients present with advanced disease, early detection seems to be one of the most important approaches to reduce mortality. Therefore, an effective screening test would have substantial clinical benefits. Furthermore, early detection of progression of disease in patients having had CRC permits immediate commencement of specific treatment regimens (e.g. curative resection of liver and lung metastases) and probably longer survival and better quality of life.

Disseminated tumor cells in peripheral blood: a novel marker for therapy response in locally advanced rectal cancer patients undergoing preoperative chemoradiation.

PURPOSE: This study was designed to examine whether disseminated tumor cells in peripheral blood of locally advanced rectal cancer patients undergoing preoperative chemoradiation have the potential to serve as a marker for therapy response. Studies suggest that patients with advanced rectal cancer who respond to preoperative chemoradiation most likely benefit from this treatment. METHODS: From advanced rectal cancer patients undergoing preoperative chemoradiation, peripheral blood was obtained at defined times: before, during, and after chemoradiation and during surgery. Patients were divided into histopathologic responders (ypT0-T2) and nonresponders (ypT3-T4). Cytokeratin 20 and carcinoembryonic antigen reverse transcriptase-polymerase chain reaction were performed to detect disseminated tumor cells. A blood sample was deemed positive for disseminated tumor cells if both carcinoembryonic antigen and cytokeratin 20 were detected. RESULTS: The overall population (n = 26) showed a positivity rate of 32 percent for disseminated tumor cells before initiation of chemoradiation. Of the responders (n = 8), 63 percent were positive for disseminated tumor cells before chemoradiation, whereas only 18 percent of nonresponders (n = 18) were positive (P = 0.026). From initiation of chemoradiation to the end of surgery, a significant decrease was seen in tumor cell positivity in the blood of responders (P = 0.042). Moreover, the responders represented a trend toward a decrease in tumor cell positivity during chemoradiation (P = 0.079). In contrast, there were no noticeable alterations within the treatment course in nonresponders. CONCLUSIONS: This prospective proof of principle study demonstrates that locally advanced rectal cancer with preoperative chemoradiation shows different biologic behavior in terms of tumor cell dissemination in peripheral blood when therapy responders compared with nonresponders.

Circulating nucleic acids in plasma or serum (CNAPS) as prognostic and predictive markers in patients with solid neoplasias.

It is now widely accepted that there is a need for the development of molecular markers of cancer that can be used for clinical prognostication and monitoring. Approximately a decade ago tumor-derived circulating nucleic acids in the plasma or serum (CNAPS) of cancer patients were introduced as a noninvasive tool for cancer detection. This review focuses on the various types of CNAPS of patients with solid neoplasias (genetic alterations in circulating DNA, microsatellites, methylated DNA, viral DNA, nucleosomes, mitochondrial DNA and cell-free mRNA) and their putative potential as prognostic or predictive parameter or even as a tool for therapy monitoring during follow-up. Additionally, this review aims to point out the difference between a prognostic and a predictive factor in patient bloodstream. However, with rapid technical improvement and well-designed studies we conclude that the next years will see CNAPS analysis integrated in the prognostication and monitoring of cancer patients, thus producing more specific treatment regimens for patients with various stages of neoplastic disease and ultimately longer survival and better quality of life.

DNA hypomethylation and ovarian cancer biology.

Hypomethylation of some portions of the genome and hypermethylation of others are very frequent in human cancer. The hypomethylation often involves satellite 2 (Sat2) DNA in the juxtacentromeric (centromere-adjacent) region of chromosome 1. In this study, we analyzed methylation in centromeric and juxtacentromeric satellite DNA in 115 ovarian cancers, 26 non-neoplastic ovarian specimens, and various normal somatic tissue standards. We found that hypomethylation of both types of satellite DNA in ovarian samples increased significantly from non-neoplastic toward cancer tissue. Furthermore, strong hypomethylation was significantly more prevalent in tumors of advanced stage or high grade. Importantly, extensive hypomethylation of Sat2 DNA in chromosome 1 was a highly significant marker of poor prognosis (relative risk for relapse, 4.1, and death, 9.4) and more informative than tumor grade or stage. Also, comparing methylation of satellite DNA and 15 5' gene regions, which are often hypermethylated in cancer or implicated in ovarian carcinogenesis, we generally found no positive or negative association between methylation changes in satellite DNA and in the gene regions. However, hypermethylation at two loci, CDH13 (at 16q24) and RNR1 (at 13p12), was correlated strongly with lower levels of Sat2 hypomethylation. The CDH13/Sat2 epigenetic correlation was seen also in breast cancers. We conclude that satellite DNA hypomethylation is an important issue in ovarian carcinogenesis as demonstrated by: (a) an increase from non-neoplastic tissue toward ovarian cancer; (b) an increase within the ovarian cancer group toward advanced grade and stage; and (c) the finding that strong hypomethylation was an independent marker of poor prognosis.