Objective To review the state of the art as reflected in the medical literature and the consensus opinion of recognized experts in the field regarding the laboratory monitoring of unfractionated heparin therapy. Data sources, extraction and synthesis The authors made an extensive review of the literature. The draft manuscript was circulated to every participant in the consensus conference prior to the convening of the conference. Extensive discussion concerning all of the issues addressed in the manuscript as well as the resulting recommendations occurred. This information was then used to revise the manuscript into its final form. Conclusions The resulting manuscript has 23 specific recommendations regarding preanalytic, analytic, and postanalytic phases of monitoring and testing for complications related to unfractionated heparin therapy. This report contains detailed discussion of these recommendations and includes literature citations that support them. A number of issues for which consensus could not be reached are also discussed. A method is provided to assist laboratories, particularly small laboratories, in providing clinicians with an appropriate therapeutic range for the activated partial thromboplastin time, the most commonly used test in monitoring heparin therapy.

College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of unfractionated heparin therapy

Carcinosarcoma is a malignant tumor having a mixture of carcinoma and sarcoma containing differentiated mesenchymal elements, such as malignant cartilage, bone, and skeletal muscle. These tumors have been linked histogenetically to pleomorphic carcinomas; it is unclear whether their clinical behavior is significantly different. To investigate this issue, we studied 66 cases of carcinosarcomas of the lung and compared them with cases from a previously published series of pleomorphic carcinomas. Carcinosarcomas show a male-to-female ratio of 7.25:1, with a mean and median age of 65 years. They most often present as solitary masses in the upper lobes and average 7 cm in diameter. Most (62%) were endobronchial or central tumors, whereas 38% were described as peripheral. The most frequent epithelial component was squamous cell carcinoma (46%), followed by adenocarcinoma (31%) and adenosquamous carcinoma (19%), whereas sarcomatous elements most frequently included rhabdomyosarcoma, chondrosarcoma, osteosarcoma, or combinations of these elements. Survival of patients with carcinosarcomas of lung was poor, with a 5-year survival rate of 21.3%. Of several clinical and pathologic parameters, only increased tumor size (with 6 cm as the optimal cutoff point) appeared to be related to reduced survival (p = 0.0195). In comparison with patients with pleomorphic carcinoma, patients with carcinosarcomas had no significant difference in the size of their tumors (p = 1.0), stage at presentation (p = 0.883), location in the lung (p = 0.073), or their overall survival (21.3% vs 15.0%) (p = 0.1038). A significantly greater proportion of patients with carcinosarcoma had squamous cell (p = 0.004) or adenosquamous (p = 0.016) carcinoma, whereas patients who had pleomorphic carcinoma showed a significantly greater frequency of adenocarcinoma (p = 0.029) and large cell carcinoma. The histologic differences between these two types of tumor suggest that they may be different entities with similar behavior, but additional studies are warranted to investigate this hypothesis.

Carcinosarcomas of the lung: a clinicopathologic study of 66 patients.

Randomized trial comparing partial versus complete chordal-sparing mitral valve replacement: Effects on left ventricular volume and function

After extensive investigation in preclinical studies and recent clinical trials, gene therapy has been established as a potential method to induce therapeutic angiogenesis in ischemic myocardial and limb disease. Advancements in viral and nonviral vector technology including cell-based gene transfer will continue to improve transgene transmission and expression efficiency. An alternative strategy to the use of transgenes encoding angiogenic growth factors is therapy based on transcription factors such as hypoxia-inducible factor-1alpha (HIF-1alpha) that regulate the expression of multiple angiogenic genes. Further understanding of the underlying biology of neovascularization is needed to determine the ability of growth factors to induce functionally significant angiogenesis in patients with atherosclerotic disease and associated comorbid conditions including endothelial dysfunction, which may inhibit blood vessel growth. The safety and tolerability of therapeutic angiogenesis by gene transfer has been demonstrated in phase I clinical trials. However, limited evidence of efficacy resulted from early phase II studies of angiogenic gene therapy for ischemic myocardial and limb disease. The utility of therapeutic angiogenesis by gene transfer as a treatment option for ischemic cardiovascular disease will be determined by adequately powered, randomized, placebo-controlled phase II and III clinical trials.

http://www.angiogenesis-center.org/documents/gene%20therapy%20paper-khan.pdf

Gene therapy progress and prospects: therapeutic angiogenesis for limb and myocardial ischemia

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1538-7836.2007.02717.x

Evaluation of aprotinin and tranexamic acid in different in vitro and in vivo models of fibrinolysis, coagulation and thrombus formation

Objective. Bronchopul- monary carcinosarcoma is a very rare tumor and the prognosis of pa- tients with carcinosarcoma is as- sessed as unfavourable. The prob- lems concerning diagnosis, therapy, and prognosis after resection treat- ment are discussed with reference to our seven cases and with considera- tion of the pertinent literature. Methods. The retrospective data of seven patients with pulmonary car- cinosarcoma were analysed. All were staged postoperatively according to the international TNM staging system. The diagnosis was verified by immunohistochemical investiga- tion. The prognosis of the patients with carcinosarcoma was compared with the prognosis of patients with non-small cell carcinoma of the lung.

Pulmonary carcinosarcoma: diagnostic problems and determinants of the prognosis.

Fibrosing mediastinitis is the most often observed benign cause of mediastinal compression syndromes, particularly the vena cava superior syndrome. We report 3 cases with such compression syndromes (2 x superior vena cava syndrome, 1 x symptomatic tracheal obstruction) due to fibrosing mediastinitis in which tumor resection led to a relief of symptoms. The operative procedures performed in our cases and in general as well as conservative treatment modalities reported for this rare disease are discussed with respect to our own experience and that of the recent publications in the European and American literature.

Mediastinal compression syndromes due to idiopathic fibrosing mediastinitis--report of three cases and review of the literature.

Objective: The cytokine vascular endothelial growth factor (VEGF) is capable of triggering angiogenesis and at higher concentrations vasculogenesis. We report on a pilot study where VEGF-DNA as an additional therapy to coronary artery bypass grafting was injected into the myocardium in 24 patients (pts) with proximal coronary artery stenosis and diffuse peripheral disease. One region of the myocardium with proven ischemia remained unsupplied after surgery because the respective epicardial coronary artery was not graftable. Methods and results: Plasmid DNA encoding for the 165- and 167-amino acid isoform of the human VEGF genes was injected directly into the myocardium, not amenable to surgical revascularization at a dosage of 1000 mg each, using a standardized protocol. A 99m Tc-sestamibiSPECT at rest performed 7 days prior to the operation, had shown decreased marker activity in the region of interest. Controls were made 1 week and 80–100 days postoperatively. Transmural scaring was ruled out intraoperatively. Coronary and left ventricular angiographies were performed preoperatively and 3 months postsurgery, respectively. One or more of the following angiographic items were found in 16/24 patients postoperatively. (1) Improvement of regional left ventricular function at the VEGF treated myocardial sector (5/24 pts). (2) Newly visible vessels considered as collaterals (8/24 pts). (3) Earlier filling of parent vessels (6/24 pts). (4) An increase in diameter of preoperatively existing collateral vessels (7/24). An increased perfusion at rest in the region of gene application was detected in 3/24 patients by early postoperative 99m Tc-sestamibi-SPECT investigation. In six additional cases, local perfusion increased markedly until the late examination. No perioperative myocardial infarctions and no signs of inflammation were observed. Newly developed abnormal vasculature was not detected in any patient. Conclusions: Direct intramyocardial administration of VEGF165-DNA and VEGF167-DNA may result occasionally in an enhancement of collateral vascularization in regions with diffuse peripheral coronary artery disease not surgically amenable. During midterm follow-up no adverse effects of VEGF-DNA application are observed so far. The very slight midterm improvements caused us to stop further VEGF-DNA application and, in our opinion, do not justify a prospective, and randomized study with a control group. q 2001 Elsevier Science B.V. All rights reserved.

/pdf/simultaneous-surgical-revascularization-and-angiogenic-gene-18cbu9v8wv.pdf

Simultaneous surgical revascularization and angiogenic gene therapy in diffuse coronary artery disease

Since the introduction of the proteinase inhibitor aprotinin in cardiac surgery, a strong increase of the activated clotting time (ACT) during the extracorporeal circulation phase (ECC) was reported in many clinical studies, but with a lack of correlation between ACT and heparin concentration. In searching for a cause of this inconsistency we investigated different surface activators of the ACT in a clinical study. During ECC ACT was measured in parallel, using a Hemochron device and corresponding tubes (nominally 12 mg celite activator) for celite ACT, and a HemoTec device with corresponding double tubes (nominally 0.1 ml kaolin activator) for kaolin ACT. Under the conditions of ECC, the kaolin ACT values (482 +/- 145 sec) were significantly lower than the celite ACT values (985 +/- 267 sec). These results were confirmed in ex-vivo experiments using an activated partial thromboplastin time (aPTT) model. With heparin alone, aPTT activated with celite and kaolin were similar. Including aprotinin in this model, the celite aPTT showed no correlation to the heparin concentration, whereas the kaolin aPTT remained well correlated to the heparin concentration and similar to the values without aprotinin. With aprotinin alone there were no changes of the aPTT times, whereas the celite ACT times were without any correlation. Our results indicate that using kaolin instead of celite the ACT measurements under aprotinin therapy stay in the same ranges as without application of aprotinin: aprotinin has no detectable influence on kaolin-activated ACT. In our opinion, kaolin should be used as the surface activator for ACT measurements under the conditions of ECC, heparinization, and aprotinin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Celite and kaolin produce differing activated clotting times during cardiopulmonary bypass under aprotinin therapy.

Mitral valve replacement (MVR) is still associated with a relatively high mortality. To investigate the influence of chordal preservation in MVR on left ventricular size and function, we studied a series of 82 patients who underwent MVR either with (group A n = 50) or without (group B n = 32) preservation of the subvalvular structures and compared the two groups. Echocardiography was performed preoperatively, and 7 days and 3 months postoperatively. Echocardiographic investigations included left atrial and ventricular diameters, right ventricular diameters and left ventricular length. Preoperatively there were no difference between the two groups of patients. Intraoperative and postoperative management was similar in the groups. Three months postoperatively echocardiographic examinations demonstrated that chordal preservation in MVR resulted in smaller left ventricular systolic and diastolic diameters (LVESD: gr. A 43.4 +/- 7.8 mm vs gr. B 48.8 +/- 9.2 mm P < 0.05, LVEDD: 57.3 +/- 7.8 mm vs 62.9 +/- 10.5 mm P < 0.05) and a significantly decreased left ventricular length (87.1 +/- 4.2 mm in gr. A vs 97.5 +/- 5.7 mm in gr. B P < 0.05). In addition, left ventricular ejection fraction in group A was significantly improved compared to group B (54.2 +/- 11.2% vs 48.1 +/- 12.4%, P < 0.05). We conclude that chordal preservation in MVR improves left ventricular function and reduces left ventricular diameters and volumes compared to resection of the mitral subvalvular appartus and that these beneficial effects can be maintained in the postoperative course.

U Straub

Papers

Pulmonary carcinosarcoma: diagnostic problems and determinants of the prognosis.

Mediastinal compression syndromes due to idiopathic fibrosing mediastinitis--report of three cases and review of the literature.

Simultaneous surgical revascularization and angiogenic gene therapy in diffuse coronary artery disease

Celite and kaolin produce differing activated clotting times during cardiopulmonary bypass under aprotinin therapy.

Postoperative assessment of chordal preservation and changes in cardiac geometry following mitral valve replacement