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The use of mathematical and computational models for reliable predictions of tumor growth and decline in living organisms is one of the foremost challenges in modern predictive science, as it must cope with uncertainties in observational data, model selection, model parameters, and model inadequacy, all for very complex physical and biological systems. In this paper, large classes of parametric models of tumor growth in vascular tissue are discussed including models for radiation therapy. Observational data is obtained from MRI of a murine model of glioma and observed over a period of about three weeks, with X-ray radiation administered 14.5 days into the experimental program. Parametric models of tumor proliferation and decline are presented based on the balance laws of continuum mixture theory, particularly mass balance, and from accepted biological hypotheses on tumor growth. Among these are new model classes that include characterizations of effects of radiation and simple models of mechanical deformation of tumors. The Occam Plausibility Algorithm (OPAL) is implemented to provide a Bayesian statistical calibration of the model classes, 39 models in all, as well as the determination of the most plausible models in these classes relative to the observational data, and to assess model inadequacy through statistical validation processes. Discussions of the numerical analysis of finite element approximations of the system of stochastic, nonlinear partial differential equations characterizing the model classes, as well as the sampling algorithms for Monte Carlo and Markov chain Monte Carlo (MCMC) methods employed in solving the forward stochastic problem, and in computing posterior distributions of parameters and model plausibilities are provided. The results of the analyses described suggest that the general framework developed can provide a useful approach for predicting tumor growth and the effects of radiation.

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This paper presents general approaches for addressing some of the most important issues in predictive computational oncology concerned with developing classes of predictive models of tumor growth. First, the process of developing mathematical models of vascular tumors evolving in the complex, heterogeneous, macroenvironment of living tissue; second, the selection of the most plausible models among these classes, given relevant observational data; third, the statistical calibration and validation of models in these classes, and finally, the prediction of key Quantities of Interest (QOIs) relevant to patient survival and the effect of various therapies. The most challenging aspects of this endeavor is that all of these issues often involve confounding uncertainties: in observational data, in model parameters, in model selection, and in the features targeted in the prediction. Our approach can be referred to as "model agnostic" in that no single model is advocated; rather, a general approach that explores powerful mixture-theory representations of tissue behavior while accounting for a range of relevant biological factors is presented, which leads to many potentially predictive models. Then representative classes are identified which provide a starting point for the implementation of OPAL, the Occam Plausibility Algorithm (OPAL) which enables the modeler to select the most plausible models (for given data) and to determine if the model is a valid tool for predicting tumor growth and morphology (in vivo). All of these approaches account for uncertainties in the model, the observational data, the model parameters, and the target QOI. We demonstrate these processes by comparing a list of models for tumor growth, including reaction-diffusion models, phase-fields models, and models with and without mechanical deformation effects, for glioma growth measured in murine experiments. Examples are provided that exhibit quite acceptable predictions of tumor growth in laboratory animals while demonstrating successful implementations of OPAL.

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Early risk-prediction is essential to prevent cardiac allograft vasculopathy (CAV) and graft failure in heart transplant patients. We developed multivariate models to identify patients likely to experience CAV, severe CAV, and failure due to CAV, at 1, 5 and 10 years. A cohort of 172 patients was followed prospectively for 6.7 ± 3.9 years. Logistic regression models were developed and cross-validated using bootstrap resampling. Predictive markers of atherothrombosis (myocardial fibrin deposition, and loss of vascular antithrombin and tissue plasminogen activator) and arterial endothelial activation (intercellular adhesion molecule-1 expression) were measured in serial biopsies obtained within 3 months posttransplant. Most markers were univariately associated with outcome. Multivariate models showed that loss of tissue plasminogen activator was the dominant and, in most cases, only predictor of long-term CAV (p < 0.001), severe CAV (p < 0.001), and graft failure due to CAV (p < 0.001). The models discriminated patients having adverse outcomes, had particularly high negative predictive values (graft failure due to CAV: 99%, 99% and 95% at 1, 5 and 10 years) and predicted event incidence and time to event. Early absence of atherothrombotic risk identifies a patient subgroup that rarely develops CAV or graft failure, implying that this low-risk subgroup could possibly be followed with fewer invasive procedures.

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After left ventricular assist system (LVAS) placement, recipients often develop antiphospholipid antibodies (aPL) that are associated with thrombosis. Fibrin glue containing a bovine thrombin preparation is used routinely in LVAS placement surgery. We investigated whether exposure to the thrombin preparation is responsible for stimulating aPL development in LVAS recipients. Pre-LVAS and weekly post-LVAS sera from six fibrin glue-exposed LVAS recipients and five nonexposed recipients were tested by enzyme-linked immunosorbent assay for IgG, IgA, and IgM anti-phosphatidylserine (aPS), anticardiolipin (aCL), anti-phosphatidylethanolamine (aPE), and anti-phosphatidylcholine (aPC). Fibrin glue exposed recipients developed a significantly greater number of aPL than the nonexposed recipients (24 vs. 8; p = 0.0069). In particular, a higher frequency of IgG aCL (6/6 vs. 1/5; p = 0.015) and IgG aPE (4/6 vs. 0/5; p = 0.045) were noted. Exposure to the bovine thrombin component of fibrin glue seems to stimulate aPL development in LVAS recipients.

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BACKGROUND: Dacron vascular prostheses are associated with thromboembolic complications and inflammatory responses; impregnation with bovine collagen reportedly stimulates additional inflammatory/immunologic complications. The Novacor (Baxter Healthcare Corp., Oakland, CA, USA) left ventricular assist system uses Dacron inflow and collagen-impregnated Dacron outflow prostheses. METHODS: Explanted inflow and outflow prostheses were evaluated for inflammatory/immunologic, hemostatic, anticoagulant, and fibrinolytic pathways. Non-implanted prostheses immersed in whole blood or plasma were used as controls. RESULTS: Immunoglobulins and complement components were observed in all prostheses with activated macrophages being present only in implanted prostheses. Antithrombin III was observed in all prostheses whereas fibrin, tissue plasminogen activator, and alpha-2 plasmin inhibitor were present only in implanted prostheses. Endothelial and smooth muscle cells associated with vascular structures containing collagen type IV and laminin were observed solely in implanted prostheses. CONCLUSION: An inflammatory response occurs and key components of hemostatic, anticoagulant, and fibrinolytic pathways are present within implanted prostheses. These processes are accompanied by endothelial and smooth muscle cell infiltration which appear to lay the foundation for neovessel development.

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Thoracoabdominal aneurysms are the most extensive of aortic aneurysms, and their correction is associated with the greatest number of complications. The introduction of new techniques has reduced the morbidity and mortality of surgery for these formidable lesions. A description of some of these techniques, as applied to 33 patients, is summarized, and the results presented.

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PURPOSE: The purpose of this study is to describe a technique for resection of extensive thoracoabdominal aneurysms, which the authors believe will lower morbidity and mortality rates. METHODS: In an effort to minimize the risk of spinal cord ischemia, we have used a combination of sided heart bypass (left atrium to left femoral artery) with local cooling of the intercostal and visceral arteries and segmental resection of the aneurysm. Segmental resection of the aneurysm allows perfusion of the spinal cord and abdominal viscera as the proximal anastomosis is completed and as each pair of intercostal arteries is reimplanted. An attempt is made to reimplant all pairs of intercostal arteries from T8 to L2. Before the intercostal or visceral arteries are reimplanted, that segment of aorta is cooled with cold crystalloid solution. Thus no segment of the aorta is exposed to warm ischemia for more than 30 minutes. Left-sided heart bypass allows the patient's temperature to be maintained between 35 degrees C and 37 degrees C. RESULTS: We have used this technique in 23 patients with types I and II (Crawford's classification) thoracoabdominal aneurysms. Seven patients (30%) had dissections or rupture associated with their aneurysms and underwent emergency operation. One of these seven patients became paraplegic after operation, for a 4.3% incidence of paraplegia. One patient died of multiple organ failure after operation. No patient had kidney failure requiring dialysis. CONCLUSIONS: We believe that our technique allows the operation to be performed in a deliberate manner with a low incidence of paraplegia and kidney failure.

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Despite refinements in elective resection of abdominal aortic aneurysms, morbidity and mortality rates for ruptured abdominal aortic aneurysms (RAAAs) remain high. Between January 1, 1980 and December 31, 1989, we treated 208 patients with RAAAs whose mean age was 70 years. The overall mortality rate was 49.5%. Logistic regression analysis showed that three factors correlated with predicted patient survival. Patients < 70 years old had a survival rate of 65.7% compared with a survival rate of 37.4% in patients > 70 years old (p < 0.001). Among "stable" patients (preoperative blood pressure consistently > 90 mm Hg), 88.9% survived compared with 40.9% of "unstable" patients (blood pressure < 90 mm Hg) (p < 0.001). Of the patients with free intraperitoneal rupture, 38.3% survived compared with a survival rate of 79.6% of patients with rupture confined to the retroperitoneum (p < 0.001). Despite a high overall mortality rate in patients with RAAAs, surgical intervention remains the only hope for survival. We continue to advocate an aggressive surgical approach in this group of patients.

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Patch angioplasty of the internal carotid artery after endarterectomy has been advocated as a means of decreasing early postoperative carotid artery thrombosis, as well as reducing the incidence of recurrent carotid artery stenosis. Noninfectious rupture of saphenous vein patches in the early postoperative period has been reported by several authors, leading others to advocate the use of prosthetic patches. This report describes three patients in whom delayed bleeding through needle holes along the suture lines in polytetrafluoroethylene cardiovascular patches occurred between 1.5 and 4 days after operation. All patients required reexploration to control bleeding, and acute respiratory distress from tracheal compression developed in one patient. Although delayed bleeding through needle holes in polytetrafluoroethylene cardiovascular patches appears to be rare, a word of caution may be in order before advocating routine patching of the carotid artery with this particular type of patch.

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Septic complications after cardiac catheterization and percutaneous transluminal coronary artery angioplasty are distinctly uncommon. However, we have recently treated nine patients with sepsis and life-threatening complications after cardiac catheterization alone or after catheterization and subsequent percutaneous transluminal coronary angioplasty. The common denominator in all patients was either repeat puncturing of the ipsilateral femoral artery or leaving the femoral artery sheath in for 1 to 5 days after the procedure. Two patients died as a direct result of their septic complications. One death occurred in a patient in whom bacterial endocarditis with congestive heart failure developed, and the other patient had a large retroperitoneal hematoma that became secondarily infected. Infected aneurysms that were successfully treated developed in three patients. Our study suggests that colonization of the needle tract by skin flora predisposes to septic complications if repeat arterial punctures are required or if a femoral artery sheath is left in place for more than 24 hours. Patients in whom sepsis develops after these procedures should be initially treated with antibiotics effective against gram-positive organisms. CT scanning or angiography should be considered for patients with persistent sepsis, septic emboli, and abdominal or flank pain. Infected aneurysms require resection or ligation because of the propensity of these aneurysms to rupture.

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Atrial myxomas are the most common primary cardiac tumors. Typical complications include congestive heart failure, systemic emboli, or vasculitic type syndromes. Presented is a case of postpartum congestive heart failure in a 17-year-old girl. Echocardiography revealed a left atrial mass. Intraoperatively this mass was found to be extending into and occluding the left pulmonary veins. Left pulmonary infarction had occurred, and left pneumonectomy was required to completely remove the lesion. This case thus represents an unusual complication of left atrial myxoma.

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