Efficacy, toxicities, and prognostic factors of stereotactic body radiotherapy for unresectable liver metastases.

INTRODUCTION: This study aims to determine the outcomes of stereotactic body radiotherapy (SBRT) for liver metastases in patients not eligible for surgery. METHODS: This study included 31 consecutive patients with unresectable liver metastases who received SBRT between January 2012 and December 2017; 22 patients had primary colorectal cancer and nine patients had primary non-colorectal cancer. Treatments ranged from 24 Gy to 48 Gy in 3 to 6 fractions over 1 to 2 weeks. Survival, response rates, toxicities, clinical characteristics, and dosimetric parameters were evaluated. Multivariate analysis was performed to identify significant prognostic factors for survival. RESULTS: Among these 31 patients, 65% had received at least one prior regimen of systemic therapy for metastatic disease, whereas 29% had received chemotherapy for disease progression or immediately after SBRT. The median follow-up interval was 18.9 months; actuarial in-field local control rates at 1, 2, and 3 years after SBRT were 94%, 55%, and 42%, respectively. The median survival duration was 32.9 months; 1-year, 2-year, and 3-year actuarial survival rates were 89.6%, 57.1%, and 46.2%, respectively. The median time to progression was 10.9 months. Stereotactic body radiotherapy was well-tolerated, with grade 1 toxicities of fatigue (19%) and nausea (10%). Patients who received post-SBRT chemotherapy had significant longer overall survival (P=0.039 for all patients and P=0.001 for patients with primary colorectal cancer). CONCLUSION: Stereotactic body radiotherapy can be safely administered to patients with unresectable liver metastases, and it may delay the need for chemotherapy. This treatment should be considered for selected patients with unresectable liver metastases.

Cardiac responses to insulin-induced hypoglycemia in nondiabetic and intensively treated type 1 diabetic patients.

Insulin-induced hypoglycemia occurs commonly in intensively treated patients with type 1 diabetes, but the cardiovascular consequences of hypoglycemia in these patients are not known. We studied left ventricular systolic [left ventricular ejection fraction (LVEF)] and diastolic [peak filling rate (PFR)] function by equilibrium radionuclide angiography during insulin infusion (12 pmol. kg(-1). min(-1)) under either hypoglycemic (approximately 2.8 mmol/l) or euglycemic (approximately 5 mmol/l) conditions in intensively treated patients with type 1 diabetes and healthy nondiabetic subjects (n = 9 for each). During hypoglycemic hyperinsulinemia, there were significant increases in LVEF (DeltaLVEF = 11 +/- 2%) and PFR [DeltaPFR = 0.88 +/- 0.18 end diastolic volume (EDV)/s] in diabetic subjects as well as in the nondiabetic group (DeltaLVEF = 13 +/- 2%; DeltaPFR = 0.79 +/- 0.17 EDV/s). The increases in LVEF and PFR were comparable overall but occurred earlier in the nondiabetic group. A blunted increase in plasma catecholamine, cortisol, and glucagon concentrations occurred in response to hypoglycemia in the diabetic subjects. During euglycemic hyperinsulinemia, LVEF also increased in both the diabetic (DeltaLVEF = 7 +/- 1%) and nondiabetic (DeltaLVEF = 4 +/- 2%) groups, but PFR increased only in the diabetic group. In the comparison of the responses to hypoglycemic and euglycemic hyperinsulinemia, only the nondiabetic group had greater augmentation of LVEF, PFR, and cardiac output in the hypoglycemic study (P < 0.05 for each). Thus intensively treated type 1 diabetic patients demonstrate delayed augmentation of ventricular function during moderate insulin-induced hypoglycemia. Although diabetic subjects have a more pronounced cardiac response to hyperinsulinemia per se than nondiabetic subjects, their response to hypoglycemia is blunted.

Day-to-day reproducibility of mental stress-induced abnormal left ventricular function response in patients with coronary artery disease and its relationship to autonomic activation.

BACKGROUND: Mental stress (MS) results in left ventricular (LV) dysfunction in approximately half of the patients with symptomatic coronary artery disease (CAD) and is an adverse prognostic sign. The reproducibility of various MS tasks in inducing LV dysfunction and its relationship to autonomic activation in patients with CAD are not known. We studied the reproducibility on different days of 3 commonly used MS tasks on LV ejection fraction (LVEF), heart rate, blood pressure, and rate-pressure product and the relationship of reproducibility to autonomic activation as determined by heart rate variability in patients with chronic stable angina. METHODS AND RESULTS: Ten patients with CAD and exercise-induced ischemia who had abnormal LVEF responses to at least one MS task from a battery of MS tasks (mental arithmetic, anger recall, and color Stroop test) while undergoing continuous ambulatory Holter and LV function monitoring underwent a second MS testing 4 to 8 weeks later, with no change in clinical status or cardiac medications in the interim. Autonomic tone was determined from indexes of heart rate variability (high frequency [HF] for parasympathetic activity and low frequency [LF] and low frequency/high frequency ratio [LF/HF] for sympathetic activity). MS tasks resulted in a small increase in heart rate (P <.0001), a modest increase in systolic blood pressure (P <.0001) and the rate-pressure product (P <.0001), and a small but statistically significant increase in LF (P <.002) and LF/HF (P <.0001), but no change in HF compared with baseline. These changes were highly reproducible over the 2 studies. With a fall in LVEF of 5% or greater considered as indicative of an MS-positive task, anger recall was the most effective and reproducible MS task in inducing LV dysfunction. MS-positive tasks were associated with a greater increase in systolic blood pressure (P =.005). Anger recall resulted in a trend toward a higher increase in systolic blood pressure (P =.08) than the other MS tasks. In MS tasks with inconsistent LVEF responses in the 2 studies (LV dysfunction present in one study but not in the other), there was significant parasympathetic withdrawal (P =.02) in MS-negative tasks but no difference in sympathetic activation. On the other hand, in MS tasks with consistent LV dysfunction on both occasions, there was no difference in parasympathetic or sympathetic activation. MS-positive tasks were not accompanied by chest pain or ST depression. CONCLUSIONS: Of the commonly used MS tasks, anger recall produces LV dysfunction with the highest frequency and is the most reproducible task when retested 4 to 8 weeks later in patients with CAD. These data are relevant for planning studies of the effects of therapeutic interventions on MS-induced LV dysfunction.

The feasibility of high-dose chemotherapy in breast cancer patients with impaired left ventricular function.

Breast cancer patients with cardiac disease are usually excluded from clinical trials of high-dose chemotherapy. We treated 52 patients with inflammatory and/or metastatic disease with sequential high-dose melphalan and stem cell rescue followed by high-dose thiotepa and stem cell rescue. Stem cells were mobilized with cyclophosphamide and/or paclitaxel and filgrastim. Left ventricular ejection fraction (LVEF) was measured by equilibrium radionuclide angiocardiography (ERNA) at baseline, after each course of chemotherapy and 4 weeks after completing both transplants. The mean absolute decrease in LVEF after the two transplants was 3.6% (P = 0. 008 for the comparison with baseline LVEF), and most of this drop (-2.5%, P = 0.007) occurred after mobilization. Unexpectedly, paclitaxel was associated with a mean absolute decrease in LVEF of 3. 4% (P = 0.032, n = 19), cyclophosphamide alone was not associated with a significant change in LVEF (-1.3%, P = 0.23), but mobilization with sequential paclitaxel and cyclophosphamide resulted in a mean absolute drop of 4.9% in LVEF (P = 0.009). Twelve patients were found to have a reduced LVEF (<50%) at least once during treatment and had a mean absolute decrease in LVEF of 10% (P = 0.008) from baseline, compared with a drop of only 1.8% (P = 0. 176) in the patients without impaired LV function. Although two of these 12 patients developed symptomatic heart failure, their cardiac symptoms were easily treated and there were no cardiac deaths. We conclude that our protocol has acceptable cardiac toxicity and breast cancer patients with impaired LV function should not be denied high-dose chemotherapy if otherwise indicated.

Heart transplant rejection with hemodynamic compromise: a multiinstitutional study of the role of endomyocardial cellular infiltrate. Cardiac Transplant Research Database.

BACKGROUND: The natural history of patients experiencing hemodynamic compromise with rejection has been incompletely characterized. This multiinstitutional study examined the outcome of such episodes, particularly with regard to the extent of cellular infiltrate on the index endomyocardial biopsy. METHODS: From January 1, 1990, through June 30, 1994, 3367 patients in the Cardiac Transplant Research Database experienced 4137 episodes of rejection. Severe hemodynamic compromise occurred in approximately 5% of the rejection episodes, and this proportion remained relatively constant over time. RESULTS: Recipient risk factors for rejection with severe hemodynamic compromise included black race, female recipient sex, and diabetes. The 3-month actuarial survival rate was 60% after rejection with severe hemodynamic compromise versus 95% after rejection with no or mild compromise. Low initial biopsy score conferred a higher early survival, but a lower survival at 2 years after rejection with severe hemodynamic compromise. Among patients who survive an initial rejection episode with severe hemodynamic compromise, survival at 2 years after an episode was 46% among those who had a low initial biopsy score versus 84% with a high biopsy score. CONCLUSIONS: Rejection with hemodynamic compromise, although rare, represents a major complication of heart transplantation with a poor long-term outcome. Survivors of hemodynamically compromising rejection episodes associated with low biopsy scores in the International Society for Heart and Lung Transplantation grading system have a significantly worse long-term outcome than survivors of episodes associated with high scores. These findings suggest that immunologic mechanisms other than lymphocytic infiltration of the cardiac allograft are important and distinct causes of allograft dysfunction.

Ultraviolet-A1 (340-400 nm) irradiation therapy in systemic lupus erythematosus.

Ultraviolet-A1 (UV-A1) wavelengths have been found effective in mitigating signs and symptoms of disease activity in systemic lupus erythematosus (SLE) but studies have been uncontrolled. To rigorously assess the effectiveness and safety of daily low-dose UV-A1 irradiation as a therapeutic agent in this disorder we enrolled 26 women with SLE in an 18-week two-phase study. During the initial six-week prospective, double-blind, placebo-controlled phase, the patients were divided into two groups; Group A was exposed to 60kJ/m2 of UV-A1 (340-400 nm) irradiation within a sunbed five days a week for three weeks and Group B was exposed for an equal amount of time to visible light of greater than > 430 nm (placebo). Each group was then crossed over for exposure to the other source for three weeks. During the second phase-2 weeks-patients and physicians were unblinded and patients were irradiated with progressively decreasing levels of UV-A1 only. Twenty-five patients completed the six-week placebo-controlled phase of the study and eighteen patients participated for the entire 18 weeks. In Group A the systemic lupus activity measure (SLAM) score improved significantly after three weeks of five-day-a-week UV-A1 irradiation (P < 0.05), regressing to baseline during the three weeks of placebo irradiation. Improvement recurred and progressed with six weeks of three-day-a-week UV-A1 irradiation (P < 0.05). Group B patients responded negligibly to the three weeks of visible light, more sharply to UV-A1, and as with Group A, maximally to the six weeks of three-day-a-week UV-A1 (P < 0.01). With twice- and then once-weekly UV-A1 irradiation the SLAM scores worsened slightly. All patients decreased their drug use. Anti-double-stranded DNA antibodies (anti-dsDNA) decreased significantly (P < 0.05) and anti-nuclear antibodies non-significantly. Side effects were negligible. Visible light had no significant effect. In conclusion, low-dose UV-A1 irradiation effectively, comfortably, and without apparent toxicity diminished signs and symptoms of disease activity in SLE.

Prognostic value of noninvasive testing one year after orthotopic cardiac transplantation.

OBJECTIVES: We sought to evaluate the prognostic value of routine noninvasive testing--stress thallium-201 imaging, rest two-dimensional echocardiography and rest equilibrium radionuclide angiography--1 year after cardiac transplantation. BACKGROUND: Coronary artery vasculopathy is the most important cause of late death after orthotopic cardiac transplantation. Several clinical variables have been identified as risk factors for development of coronary vasculopathy. Traditional noninvasive diagnostic testing has been shown to be relatively insensitive for identifying patients with angiographic vasculopathy. METHODS: Results of prospectively acquired noninvasive testing in 47 consecutive transplant recipients alive 1 year after transplantation were related to subsequent survival. Other clinical variables previously shown to be associated with the development of coronary artery vasculopathy were also included in the analysis. RESULTS: The 5-year survival rate after cardiac transplantation was 81%. By univariate analysis, echocardiography (chi-square 9.21) and stress thallium-201 myocardial perfusion imaging (chi-square 16.76) were predictive for survival, whereas rest equilibrium radionuclide angiography was not. Clinical contributors to survival were donor age (chi-square 4.56), number of human leukocyte antigen mismatches (chi-square 3.06) and cold ischemic time (chi-square 3.23). By multivariate analysis, stress myocardial imaging remained the only significant predictor of survival (risk ratio 0.27; 95% confidence interval 0.06 to 0.89). CONCLUSIONS: Normal thallium-201 stress myocardial perfusion imaging 1 year after cardiac transplantation is an important predictor of 5-year survival.

Optimal timing and indications for cholecystectomy in cardiac transplant patients.

Cardiac transplant is performed with increasing frequency as the treatment for end-stage cardiac disease. Although cholelithiasis is more frequent in both pretransplant and posttransplant patients, no standard management approach exists. Because many such patients are cared for outside the transplant center, it is important that general surgeons develop an appropriate strategy to manage this entity. We present our experience with 11 patients from our institution who underwent cholecystectomy before or after cardiac transplantation. In addition, we have reviewed the 76 reported cases of cholecystectomy performed in precardiac or postcardiac transplant patients from centers throughout the world. Any procedure in this patient group requires critical consideration in regard to the timing and type of procedure. Pretransplant patients are well recognized cardiac risks, and posttransplant immunosuppressed patients are at considerable risk for septic complications. Six patients underwent cholecystectomy prior to heart transplant. Five were performed laparoscopically, one as an open procedure. We also report five laparoscopic cholecystectomies in patients after cardiac transplant. One patient in the pretransplant group died 7 days after surgery from an uncontrollable arrhythmia. There were no hemodynamic or septic complications in either group. Current summated experience (87 cases) indicates that the mortality rate for urgent cholecystectomy in the posttransplant group is at least 36%. Because the first presentation of gallstones in this population is often acute cholecystitis, asymptomatic calculi cannot be considered benign. Elective cholecystectomy, laparoscopic or open, is tolerated well both before and after transplant. Given these facts, it seems reasonable to recommend pretransplant screening and posttransplant surveillance for gallstones.(ABSTRACT TRUNCATED AT 250 WORDS)

Medical therapy and prognosis in chronic heart failure. Lessons from clinical trials.

The past two decades have witnessed tremendous advances in the pharmacologic therapy of patients with left ventricular dysfunction and chronic heart failure. The pharmacologic repertoire has been and continues to be expanded with newer agents carefully subjected to the rigor of well-designed clinical trials. Treatment has consequently evolved from pathophysiologically guided therapy predicated on older concepts to evidence-guided therapy supported by results of major clinical trials that continue to expand the understanding of the pathophysiology of this complex syndrome. The goals of therapy have ambitiously evolved from the immediate symptomatic relief offered by diuretics; to the short-term hemodynamic improvement in the circulation produced by direct vasodilators; to the intermediate-term improvement in functional capacity and exercise tolerance associated with vasodilators, nitrates, and digoxin; and to the final frontier of long-term improvement in morbidity and survival associated with ACE inhibitor therapy. In addition to the expansion of the understanding of the epidemiology, natural history, and pathophysiology of chronic heart failure, several important lessons in clinical pharmacology have been learned from the clinical trials of the last decade. Many other questions, however, remain unanswered. The role of diuretics, although uncontested in the acute stabilization of congested patients, has yet to be rigorously evaluated in stable patients with chronic left ventricular dysfunction on ACE inhibitors. The long-term effects of nitrates on morbidity and mortality have not yet been established in patients with either ischemic or nonischemic ventricular dysfunction. Vasodilators as a class, and perhaps because they are not a homogeneous class, have had a mixture of successes and failures. There is no evidence that pure vasodilation in and by itself improves survival. There is ample evidence, however, that it improves the circulation and consequently the response to diuretics. This improvement may translate into intermediate-term improvement in functional capacity, but this benefit is seldom sustained. Hemodynamic improvement in the circulation may not always translate into longer-term improvement in morbidity and reduction in mortality. The syndrome of chronic heart failure from systolic left ventricular dysfunction has emerged as a disease of mechanical dysfunction and maladaptation. The maladaptation is a consequence of deleterious effects of compensatory neurohormonal mechanisms: the sympathetic nervous system, renin-angiotensin-aldosterone system, arginine vasopressin, and most likely a host of other mechanisms. The degree of activation of these mechanisms has been established as a marker of prognosis, and the effects of pharmacologic agents on these mechanisms may well determine their long-term effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Oxidative metabolism and mechanical function in reperfused neonatal pig heart.

Oxidative metabolism in reperfused neonatal myocardium has not been characterized. A blood-perfused isovolumic heart preparation was used to quantify metabolic and mechanical responses of the neonatal left ventricle to global normothermic ischemia and reperfusion. Hearts from piglets aged 2-7 days were subjected to either 2 hrs of total ischemia at 37 degrees C followed by 1 hr of reperfusion or 3 hrs of perfusion alone; glucose and palmitate oxidation were measured in separate experiments by incorporation of the appropriate [14C]-labeled substrate into the perfusate. In the pre-ischemic period, glucose, palmitate, and lactate contributed 10%, 41%, and 36%, respectively, to oxidative metabolism. After 2 hrs of total normothermic ischemia, oxidation of exogenous glucose was 165% and 229% of control values at 30 and 60 minutes of reperfusion, respectively; palmitate oxidation was 110% and 143% of control values at these times. Despite increased glucose oxidation, palmitate oxidation accounted for 69% of myocardial oxygen consumption after 1 hr of reperfusion, with glucose responsible for 25%. Lactate use was minimal during reperfusion. Reperfusion was accompanied by rapid and parallel recovery of oxygen utilization, mechanical function, and high-energy phosphates. The neonatal piglet heart demonstrates significant metabolic and mechanical tolerance to prolonged ischemia. Although glucose utilization increased markedly, palmitate was the primary substrate for energy production in the post-ischemic neonatal heart.

Hemodynamics of the right ventricle in normal and disease states.

The physiology and hemodynamic functions of the right ventricle in normal and disease states differ considerably from those of the left ventricle. To illuminate these differences, the right ventricle's essential functions in the normal circulation are reviewed, its functional anatomy and blood supply are described, principles and methods of systolic function assessment are discussed, and hemodynamic adaptations to selected diseases causing chronic right-side volume and pressure overload are highlighted.

A bending energy model for measurement of cardiac shape deformity.

An approach to analyzing and quantifying the shape characteristics of the endocardial contour of the left ventricle of the heart is described. The computation begins by finding the local curvature differences between the contour under consideration and the mean normal contour at each of 100 equidistant points. The weighted square of these differences, summed over a set of points, is shown to be the regional or, global bending energy required to deform the mean normal contour to the characteristic shape of the analyzed contour. Resampling, smoothing and curvature computation issues are considered for the image-derived digital contours that are used in the analysis. Experiments were performed on artificial contour data and data derived from contrast ventriculographic (CV) studies of humans. It is also shown that the method has been adapted to measure endocardial shape form equilibrium radionuclide angiocardiography.

Onset of altered interventricular septal motion during cardiac surgery. Assessment by continuous intraoperative transesophageal echocardiography.

Abnormal motion of the interventricular septum is frequently observed after uncomplicated cardiac surgery. We sought to elucidate the mechanism underlying this phenomenon by using continuous echocardiographic imaging of the heart from a constant transesophageal location in 21 patients undergoing their first cardiac operation. Quantitative global and regional functional analyses were performed in each patient at baseline (stage 1), after median sternotomy (stage 2), after sternal retraction (stage 3), after pericardiotomy (stage 4), after completion of cardiopulmonary bypass (stage 5), and after chest closure (stage 6). During the first four surgical stages, mean left ventricular fractional shortening varied little among regions with a fixed reference system (maximum range, 31.6-39.2%; p = NS) but changed dramatically after the discontinuation of cardiopulmonary bypass (stage 5). The apparent medial hypokinesis that was observed (4.9 +/- 4.7% [SD]) was accompanied by lateral hyperkinesis (65.2 +/- 4.1%, p less than 0.0001). These regional differences were completely eliminated with a floating reference system (33.6 +/- 2.7% for medial, and 34.8 +/- 1.7% for lateral; p = NS), suggesting cardiac translation. Quantitative curvature analysis supported this conclusion, with preservation of baseline regional curvature seen throughout the procedure. The mean length of individual translational vectors (reflecting systolic movement of the endocardial centroid) remained minimal (less than or equal to 1.0 mm) through stage 4 but increased more than fourfold at stage 5, continuing in a medial direction after chest closure (5.2 +/- 3.0 mm and 271 +/- 6 degrees from anterior). Thus, abnormal postoperative septal motion is not caused by removal of restraining forces of the pericardium or anterior mediastinum but rather appears to be directly related to events occurring during cardiopulmonary bypass.

Peak filling rate normalized to mitral stroke volume: a new Doppler echocardiographic filling index validated by radionuclide angiographic techniques.

The noninvasive measurement of left ventricular filling has relied predominantly on radionuclide-derived peak filling rate normalized to end-diastolic volume. Doppler echocardiography also has the ability to measure peak filling rate, but wide application of this technique has been limited by technical errors involved in quantitative echocardiographic determination of mitral anulus cross-sectional area and ventricular volumes. For Doppler echocardiography, normalization of peak filling rate to mitral stroke volume rather than end-diastolic volume permits the derivation of a diastolic filling index that is relatively free of errors caused by geometric assumptions, diameter measurements and sample volume positioning. This normalization process can be achieved by simply dividing early peak filling velocity by the time velocity integral of mitral inflow. To validate this new Doppler echocardiographic filling index, Doppler echocardiographic and radionuclide-derived peak filling rate, both normalized to mitral stroke volume, were compared in 30 patients; there was an excellent correlation (r = 0.91, SEE = 0.88). This variable was not influenced by the position of the sample volume in relation to the mitral apparatus in contrast to early filling velocity, which increased 37%, and early/late filling (E/A) ratio, which increased 43% as the sample volume was moved from the anulus to the tips of the mitral leaflets. In a cohort of 22 normal patients, the mean peak filling rate normalized to mitral stroke volume (SV) was 5.25 +/- 1.47 SV/s. The mean peak filling rate for a subgroup of eight normal patients aged 57 to 89 years (mean 71 +/- 9) was 3.9 +/- 1 SV/s.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of the hemodynamically unstable patient.

The pathogenesis, diagnosis, and management of six clinical syndromes associated with acute myocardial infarction and hemodynamic instability are discussed: (1) autonomic disturbances with hypertension-tachycardia or hypotension-bradycardia; (2) pulmonary edema; (3) cardiogenic shock; (4) right ventricular infarction; (5) rupture of ventricular free wall or septum; and (6) papillary muscle rupture.