Role of matrix metalloproteinases in mitral valve regurgitation: Association between the of MMP-1, MMP-9, TIMP-1, and TIMP-2 expression, degree of mitral valve insufficiency, and pathologic etiology.

BACKGROUND: The pathogenesis of mitral valve insufficiency is not yet fully understood. Several studies stressed the role of matrix metalloproteinases (MMPs) in the emergence of valvular pathologies. The primary objective of the present study is to analyze the role of selected MMPs and their inhibitors in mitral valve insufficiency. PATIENTS AND METHODS: Eighty patients (33 female/47 male, mean age 67 years) underwent cardiopulmonary bypass surgery for mitral valve reconstruction between 2007 and 2015. All patients suffered from mitral insufficiency (MI) Stages iii and iv. When tissue resection was acquired specimens were taken immediately frozen and used for histological examination. Expression of MMP-1, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 was examined immunohistochemically and distribution was analyzed in regard to preoperative clinical, echocardiographic, and histopathological findings. RESULTS: A clear correlation between the MMP expression and the MI degree of severity could be shown. The expression of MMPs proved to be high in relation to mild insufficiencies and relatively weak in the case of severe ones. Additionally, the etiology of the MI was considered in the analysis and a significant difference in the expression of MMPs between the mitral valves with endocarditis and the ones featuring a degenerative disease could be shown. Within the group of valves with degenerative diseases, no significant difference could be established between the subgroups (myxoid and sclerosed valves). CONCLUSION: The increased expression of MMPs and their inhibitors in mild insufficiencies could prove that the molecular changes in the valve precede the macroscopical and thus the echocardiographically diagnosable changes. Hence, new options for early diagnosis and therapy of MIs should be examined in further studies, respectively. Herein, the correlation of the MMP blood levels with MMP tissue expression should be addressed for surgical therapeutical decisions.

Histological validation of pulmonary infarction detected with contrast-enhanced ultrasound in patients with negative computed tomography pulmonary angiogram: A case series.

OBJECTIVE: The purpose of this case series is to evaluate the diagnostic potential of contrast-enhanced ultrasound (CEUS) in patients with clinically suspected pulmonary embolism (PE), suspicious pleural lesions, and negative computed tomography pulmonary angiogram (CTPA). PATIENTS/METHODS: Between January 2017 and January 2018, we examined patients with an intermediate or a high-risk Wells score and a negative CTPA with lung B-mode ultrasound (LUS). In a total of six patients, pleural defects were identified and further examined by CEUS. Nonenhancing lesions or those with inhomogeneous enhancement were considered to be suspicious for an embolic event and biopsied for histological validation. The data analysis was retrospective. RESULTS: In LUS, the lesions had an average size of 2.4 cm (range 2-3 cm). Five were hypoechoic and one was complex. The shape was wedge shaped (n = 5) or round (n = 1), and the number was solitary (n = 4) or multiple (n = 2) with dorsobasal localization (n = 6). Three lesions were nonenhancing, and three had an inhomogeneous enhancement with areas with complete absence of enhancement. The histological examination showed pulmonary infarction in all six cases, and in one patient also cells of a lung carcinoma. CONCLUSION: Our case series demonstrates the diagnostic potential of CEUS for detecting peripheral pulmonary infarction in patients with clinically suspected PE and negative CTPA scan regarding PE. A histological validation or a narrow follow-up might be warranted in some cases.

A Newly Developed mm-Wave Sensor for Detecting Plaques of Arterial Vessels.

BACKGROUND: Microcalcifications within the fibrous cap of the arteriosclerotic plaques lead to the accrual of plaque-destabilizing mechanical stress. New techniques for plaque screening with small detectors and the ability to differentiate between the smooth and hard elements of plaque formation are necessary. METHOD: Vascular plaque formations are characterized as calcium phosphate containing structures organized as hydroxylapatite resembling the mineral whitlockite. In transmission and reflexion studies with a simple millimeter wave (mm-wave)-demonstrator, we found that there is a narrow window for plaque detection in arterial vessels because of the tissue water content, the differentiation to fatty tissue, and the dielectric property of air or water, respectively. RESULT: The new sensor is based on a sensing oscillator working around 27 GHz. The open-stub capacitance determines the operating frequency of the sensor oscillator. The capacitance depends on the dielectric properties of the surrounding material. The sensor components were completely built up in surface mount technique. CONCLUSION: Completed with a catheter, the sensor based on microwave technology appears as a robust tool ready for further clinical use.

Retinoic acid inhibits angiogenesis and tumor growth of thyroid cancer cells.

The anti-proliferative effect of retinoic acid (RA) has been documented for various tumors. Some 40% of patients with advanced and poorly differentiated thyroid cancer have been shown to respond to RA with increased uptake of radioiodine. It has been suggested that these effects may be caused by redifferentiation. Presently, little is known about the effects of RA on tumor angiogenesis, a prerequisite for growth and metastatic spread. The aim of the current study was to determine, whether tumor-induced angiogenesis of thyroid cancer is affected by RA. In vitro, the effect of 0.1/10 microM 13-cis RA on tumor cell number (MTT assay) and secretion of VEGF (ELISA) was analyzed in three thyroid cancer cell lines (FTC 236, C634 and XTC), as well as in endothelial cells (HUVEC) over several passages. In vivo, tumor growth, VEGF-expression and microvessel density (VSD) of RA treated thyroid cancer cells after xenotransplantation to nude mice was evaluated by morphometric analysis. In vitro, thyroid cancer cell lines responded to RA with reduced proliferation, ranging from 26 to 34% after 2 weeks of treatment and with up to 80% reduced secretion of VEGF. In vivo, tumor volumes of animals receiving RA were reduced by 33% (FTC 236), 27% (C643) and 6% (XTC), respectively. VSD of experimental tumors was diminished in the FTC 236 (25%) and the C643 cell line (15%), and almost unchanged in XTC tumors (7%). In vivo, VEGF-expression and apoptosis were not significantly affected by RA. In vitro, proliferation of HUVEC was inhibited by conditioned medium of C643 cells pretreated with RA (0.1/10 microM), as well as by administration of RA (0.1/10 microM). This study confirms thyroid tumor cell growth to be inhibited by RA. It demonstrates a decrease of in vitro VEGF accumulation and reduction of VSD in experimental undifferentiated thyroid carcinoma, suggesting that reduced angiogenesis may be an important mechanism responsible for the therapeutic effect of RA in thyroid cancer. Moreover, a direct anti-proliferative effect of RA on human endothelial cells is suggested.

Detailed Measurement of Wall Strain with 3D Speckle Tracking in the Aortic Root: A Case of Bionic Support for Clinical Decision Making.

Three-dimensional (3D) wall motion tracking (WMT) based on ultrasound imaging enables estimation of aortic wall motion and deformation. It provides insights into changes in vascular compliance and vessel wall properties essential for understanding the pathogenesis and progression of aortic diseases. In this report, we employed the novel 3D WMT analysis on the ascending aorta aneurysm (AA) to estimate local aortic wall motion and strain in case of a patient scheduled for replacement of the aortic root. Although progression of the diameter indicates surgical therapy, at present we addressed the question for optimal surgical time point. According to the data, AA in our case has enlarged diameter and subsequent reduced circumferential wall strain, but area tracking data reveals almost normal elastic properties. Virtual remodeling of the aortic root opens a play list for different loading conditions to determine optimal surgical intervention in time.

Mutations and polymorphisms in the SDHB, SDHD, VHL, and RET genes in sporadic and familial pheochromocytomas.

The prevalence of germ line mutations within the RET-protooncogene and the tumor suppressor genes SDHB, SDHD, and VHL in pheochromocytomas (PC) varies in recent studies from 12 to 24%, if one look at them collectively. DNA was extracted from frozen tumor tissue as well as from blood leukocytes of 36 PC (26 sporadic/10 MEN2). Exons 1-8 of the SDHB-gene, 1-4 of the SDHD-gene, 1-3 of the VHL-gene, and exons 10, 11, 13, 14, 16 of the RET-gene were amplified by PCR and analyzed by DHPLC with the Transgenomic WAVE-System. Samples with aberrant wave profiles were subjected to direct sequencing. Genetic aberrations were correlated to clinical characteristics. Germ line mutations in sporadic PC were identified in four patients (11%) whereas somatic mutations were observed in two (5%) patients. Nine coding polymorphisms (PM) were identified in seven (19%) patients. Intronic variants were observed in six (17%) patients and were all located in the SHDB gene. Patients with wild type alleles in all assessed genes were older (53 vs. 37 years, P = 0.007) and presented with an increased tumor size (49 vs. 32 mm, P = 0.003) compared to patients with mutations. Malignant PC revealed multiple (>2) genetic alterations more frequently than benign PC (4/7 vs. 4/29, P = 0.03). Interestingly intronic variants of the SDHB gene occur more frequently in malignant than in benign PC (3/7 vs. 2/29, P = 0.04). The frequency of germ line mutations in sporadic pheochromocytomas was lower in our cohort than previously reported. Polymorphisms of the RET gene are common (17%) and occur in familial and sporadic PC. Multiple genetic alterations including mutations, polymorphisms and intronic variants are more frequently observed in malignant PC.

An aggressive surgical approach leads to long-term survival in patients with pancreatic endocrine tumors.

OBJECTIVE: To evaluate the outcome of reoperations in patients with duodenopancreatic neuroendocrine tumors (PETs) in a tertiary referral center. SUMMARY BACKGROUND DATA: The management of reoperations in PETs is still controversial. METHODS: A total of 125 patients with PETs that underwent surgery between 1987 and 2004 at our institution were retrospectively evaluated. The diagnosis of PETs was based on clinical symptoms, biochemical tests, and histopathology. Patients with at least one reoperation were analyzed regarding clinical characteristics, pathology, operations, and long-term follow-up. RESULTS: A total of 33 patients with a median age of 42 years were identified for this study: 13 patients had gastrinomas, 12 patients had nonfunctional islet cell tumors, 6 patients had insulinomas, and 2 patients had vipomas; 24 patients had sporadic NETs, 9 patients had a MEN-1-syndrome; 27 patients had histologically verified malignant tumors; 33 initial operations and 50 reoperations were performed. The initial procedures comprised 27 resections of the primary tumor and 6 explorative laparotomies; 28 of all reoperations were resections of distant metastases, including 15 liver resections; 19 resections of the pancreas or duodenum were performed during reoperations. The overall morbidity and mortality was 45% and 4.8%, respectively. After a median follow-up of 124 months (range, 16-384 months), 27 of 33 patients are still alive, 12 without evidence of disease. All 6 patients with benign tumors are still alive. The 5-, 10-, and actuarial 25-year survival rate for patients with malignant tumors were 81%, 72%, and 36%, respectively. The survival rate was significantly related to the patients age at time of initial operation and better in patients younger than 50 years compared with patients older than 50 years (P = 0.0007), and the presence or development of metastases (none or lymph node metastases versus distant metastases: P = 0.01). CONCLUSION: We show that an aggressive surgical approach leads to long-term survival in patients with malignant PETs. Although long-term cure can only be achieved in a proportion of patients with malignant PETs, significant long-term palliation can be achieved.

The sentinel node concept in head and neck cancer: solution for the controversies in the N0 neck?

BACKGROUND: The majority of patients with head and neck squamous cell carcinoma (HNSCC) who have a clinical N0 neck undergo neck dissection (ND) even though no lymph node metastases may be detected. With this background, our investigation critically analyzes the value of sentinel lymphadenectomy. METHODS: Ninety patients with HNSCC, all staged with an N0 neck, underwent intraoperative 99mTc-radiolabeled detection of up to three hot nodes (SN1-3) during elective ND and primary site resection. RESULTS: Sentinel lymphadenectomy (SN1-3) detected occult metastatic spread in 20 (22%) of 90 patients, whereas failure occurred in three of 90 patients. Metastatic spread was directed to level II in the majority (66.7%) of cases. If only the SN1 had been examined, the procedure would have failed in nine (39%) of 23 patients. CONCLUSION: Sentinel lymphadenectomy correctly identified the stage of metastatic disease in 97% of patients in cases in which up to three sentinel nodes were identified. If only the lymph node with the highest tracer activity had been excised, 39% of cancer-positive necks would have been missed. Selective ND identified metastatic disease in the additional 3% of patients.