Leukemia-cell proliferation and disease progression in patients with early stage chronic lymphocytic leukemia.

The clinical course of patients with recently diagnosed early stage chronic lymphocytic leukemia (CLL) is highly variable. We examined the relationship between CLL-cell birth rate and treatment-free survival (TFS) in 97 patients with recently diagnosed, Rai stage 0-II CLL in a blinded, prospective study, using in vivo 2H2O labeling. Birth rates ranged from 0.07 to 1.31% new cells per day. With median follow-up of 4.0 years, 33 subjects (34%) required treatment by NCI criteria. High-birth rate was observed in 44% of subjects and was significantly associated with shorter TFS, unmutated IGHV status and expression of ZAP70 and of CD38. In multivariable modeling considering age, gender, Rai stage, expression of ZAP70 or CD38, IGHV mutation status and FISH cytogenetics, only CLL-cell birth rate and IGHV mutation status met criteria for inclusion. Hazard ratios were 3.51 (P=0.002) for high-birth rate and 4.93 (P<0.001) for unmutated IGHV. The association between elevated birth rate and shorter TFS was observed in subjects with either mutated or unmutated IGHVs, and the use of both markers was a better predictor of TFS than either parameter alone. Thus, an increased CLL birth rate in early stage disease is a strong predictor of disease progression and earlier treatment.

Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia.

We examined the combination of the mammalian target of rapamycin inhibitor everolimus with bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM) in a phase I/II study. All patients received six cycles of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab followed by maintenance with everolimus until progression. Forty-six patients were treated; 98% received prior rituximab and 57% received prior bortezomib. No dose-limiting toxicities were observed in the phase I. The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs. Of these 36, 2 (6%) had complete response (90% confidence interval (CI): 1-16). In all, 32/36 (89%) of patients experienced at least a minimal response (90% CI: 76-96%). The observed partial response or better response rate was 19/36 (53, 90 CI: 38-67%). For the 36 FDT patients, the median progression-free survival was 21 months (95% CI: 12-not estimable). In summary, this study demonstrates that the combination of everolimus, bortezomib and rituximab is well tolerated and achieved 89% response rate even in patients previously treated, making it a possible model of non-chemotherapeutic-based combination therapy in WM.

Radiation responses of perfused tracheal tissue.

We are using a novel perfusion system to examine the effects of radiation on a model respiratory tissue. Tracheas taken from young adult male Fischer 344 rats are embedded in a growth factor-enriched agarose matrix that is mounted in a special apparatus designed to allow growth medium to periodically wash the epithelial surface of the lumen. A comparison of the microarray expression profiles of freshly harvested tracheas and tracheas maintained in perfusion culture for 24 h shows no significant difference except for an increase in expression of a few metabolism- and surfactant-related genes. Perfusion culture samples exposed to 4 Gy of X rays show a lower than expected increase in expression for some cell cycle- and repair-related genes.

Helpful hints for endoscopic biliary stenting.

At Duke University Medical Center approximately 1,000 endoscopic retrograde cholangiopancreatography procedures are completed per year. Hints for biliary stenting have been developed. This article is meant to provide the GI nurse/associate with a quick reference when assisting with stent placement.

Effects of electrophysiologic testing of the automatic implantable cardioverter-defibrillator on left ventricular systolic function and diastolic filling.

We investigated the effects of electrophysiologic testing of the automatic implantable cardioverter-defibrillator (AICD) on left ventricular systolic function and diastolic filling in 12 patients. Ventricular tachycardia or ventricular fibrillation was induced by programmed electrical stimulation and alternating-current, respectively. Patients were studied before and immediately after, 10 minutes after, and 1 hour after defibrillation by the AICD using M-mode, two-dimensional, and pulsed Doppler echocardiography. Immediately after defibrillation, increases were found in the peak early filling velocity (70 +/- 10 cm/sec to 84 +/- 24 cm/sec, p less than 0.01), peak early-to-atrial filling velocity ratio (1.05 +/- 0.21 to 1.29 +/- 0.26, p less than 0.005), and maximum rate of diastolic chamber enlargement (82 +/- 26 mm/sec to 102 +/- 44 mm/sec, p less than 0.05). These changes were not evident at 10 minutes and 1 hour. Cardiac output and ejection fraction were unchanged after defibrillation. Heart rate and diastolic filling time were unchanged. We conclude that electrophysiologic testing of the AICD does not impair left ventricular function in the immediate to 1-hour period after defibrillation. Left ventricular systolic function is unchanged and diastolic filling is enhanced.

Usefulness of serial pulmonary function testing as an indicator of amiodarone toxicity.

A prospective study was conducted of 189 patients treated with amiodarone, maintained at doses of 400 to 800 mg/day and followed for up to 6 years. Only patients who had life-threatening ventricular arrhythmias unresponsive to conventional therapy were enrolled, and they underwent baseline pretreatment pulmonary function tests, with follow-up testing every 6 months. Morbidity and mortality statistics were confirmed by chart review and patient telephone interview. Of the 189 enrolled patients, 101 are alive, 84 are dead and 4 are lost to follow-up. Amiodarone-induced toxicity to the neurologic system, lungs, thyroid or liver was the primary or complicating cause of death in 12 of the 84 patients who died. The overall prevalence of all these forms of toxicity was 15%. Sixty-nine percent of the patients with amiodarone toxicity had pulmonary toxicity alone or combined with other forms of toxicity. Pulmonary function test abnormalities were noted at baseline in 75% of patients who had amiodarone-induced toxicity. The proportion of abnormal baseline pulmonary function tests was not significantly different among all toxic patients, pulmonary toxic patients and nontoxic patients. An evaluation of the decrease in pulmonary function over time could not distinguish patients who developed toxicity from those who did not. The observed incidence of pulmonary toxicity is consistent with published values; however, contrary to the findings of others, no statistically significant differences in pulmonary function at baseline or in changes over time were found between toxic and nontoxic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Natural history of potentially lethal ventricular arrhythmias in patients treated with long-term antiarrhythmic drug therapy.

To examine the natural history of long-term anti-arrhythmic therapy in patients with benign and potentially lethal ventricular premature complexes (VPCs), 28 patients with initial efficacy with moricizine (greater than 75% suppression of baseline mean VPCs/hr and greater than 90% suppression of repetitive VPCs) were prospectively followed for 1 to 56 (mean +/- standard deviation 25 +/- 17) months. Patients were examined during baseline placebo, anti-arrhythmic drug therapy and intermittent pulsed-placebo reexamination periods. The mean VPCs of all patients at baseline entry were 233 +/- 47 VPCs/hr, and after moricizine therapy 14 +/- 4 VPCs/hr. Follow-up demonstrated that antiarrhythmic efficacy decreased to 75% at 12 months and to 62% at 24 months. Loss of antiarrhythmic drug efficacy most commonly occurred as a "transient" event (10 patients [36%]), and efficacy was spontaneously reestablished without a change in antiarrhythmic therapy. In contrast, increased dose titration of moricizine was necessary to reestablish antiarrhythmic suppression efficacy in 4 patients (14%), and 4 patients (14%) lost antiarrhythmic drug responsiveness during follow-up. Spontaneous decrease in baseline VPCs resulted in discontinuation of antiarrhythmic therapy in 3 patients, and increase in baseline VPCs was associated with a loss of antiarrhythmic response in 2 patients. Late proarrhythmic effects (2 patients, 7%), delayed side effects necessitating drug withdrawal (6 patients, 21%) and medical events (4 patients, 14%) occurred during 56 months of follow-up. Individual serum moricizine levels remained in the therapeutic range throughout the study and did not correlate with changes in antiarrhythmic efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

The hemodynamic benefit of differential atrioventricular delay intervals for sensed and paced atrial events during physiologic pacing.

The ability to program different atrioventricular (AV) delay intervals for paced and sensed atrial events is incorporated in the design of some newer dual chamber pacemakers. However, little is known regarding the hemodynamic benefit of differential AV delay intervals or the magnitude of difference between optimal AV delay intervals for paced and sensed P waves in individual patients. In this study, Doppler-derived cardiac output was used to examine the optimal timing of paced and sensed atrial events in 24 patients with a permanent dual chamber pacemaker. The hemodynamic effect of utilizing separate optimal delay intervals for sensed and paced events compared with utilizing the same fixed AV delay interval for both was determined. The optimal delay interval during DVI (AV sequential) pacing and VDD (atrial triggered, ventricular inhibited) pacing at similar heart rates was 176 +/- 44 and 144 +/- 48 ms (p less than 0.002), respectively. The mean difference between the optimal AV delay intervals for sensed (VDD) and paced (DVI) P waves was 32 ms and was up to 100 ms in some individuals. The difference between optimal AV delay intervals for sensed and paced atrial events was similar in patients with complete heart block and those with intact AV node conduction. At the respective optimal AV delay intervals for sensed and paced P waves, there was no significant difference in the cardiac output during VDD compared with DVI pacing. However, cardiac output significant declined during VDD pacing at the optimal AV delay interval for a paced event and during DVI pacing at the optimal interval for a sensed event.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic benefit of atrioventricular synchrony: prediction from baseline Doppler-echocardiographic variables.

The purpose of this study was to determine if baseline Doppler-echocardiographic variables of systolic or diastolic function could predict the hemodynamic benefit of atrioventricular (AV) synchronous pacing. Twenty-four patients with a dual chamber pacemaker were studied. Baseline M-mode and two-dimensional echocardiograms were obtained and Doppler-echocardiographic measurements of mitral inflow and left ventricular outflow were made in VVI mode (single rate demand) and in VDD (atrial synchronous, ventricular inhibited) and DVI (AV sequentially paced) modes at AV intervals ranging from 50 to 300 ms. Forward stroke volume and cardiac output were determined in each mode at each AV interval from the left ventricular outflow tract flow velocities, and the percent increase in cardiac output over VVI mode was determined. M-mode measurements, including left ventricular end-diastolic dimension, shortening fraction and left atrial size and Doppler measurement of diastolic filling, including peak early velocity and percent atrial contribution, did not correlate with the percent increase in cardiac output during physiologic pacing. The stroke volume in VVI mode correlated significantly with the percent increase in cardiac output during physiologic pacing (r = -0.61, p less than 0.005 for VDD mode and r = -0.55, p less than 0.05 for DVI mode). Five of the 15 patients with VVI stroke volume less than 50 ml but none of the 9 patients with stroke volume greater than 50 ml had ventriculoatrial (VA) conduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Morton neuroma: sonographic evaluation.

One hundred consecutive patients with symptoms suggestive of Morton neuroma were examined with sonography, and 134 intermetatarsal masses were demonstrated. Forty-five patients underwent surgical exploration, which revealed Morton neuromas. The typical sonographic appearance is that of an ovoid, hypoechoic mass oriented parallel to the long axis of the metatarsals. Most masses were between the second and third or third and fourth metatarsals and seemed to produce symptoms when reaching a diameter of 5 mm.

Emergency catheter ablation of refractory ventricular tachycardia.

Catheter ablation, in extreme cases, can be used successfully as emergency therapy for VT in the CCU. In the hands of a physician experienced in electrophysiologic procedures, catheter ablation may prove to be an alternative to surgical or pharmacologic therapy in acutely ill patients with refractory ventricular arrhythmias.

Effects of electrophysiologic studies resulting in electrical countershock or burst pacing on left ventricular systolic and diastolic function.

To determine the acute effects of electrophysiologic study on left ventricular systolic and diastolic function in patients requiring termination of induced tachyarrhythmias by either electrical countershock or burst pacing, we examined 16 patients (11 men and five women), aged 43 to 78 years (mean 58 +/- 13), undergoing programmed electrical stimulation. Indices of systolic and diastolic left ventricular function were measured by M-mode echocardiography before and within 1 minute after termination of 22 episodes of induced tachyarrhythmias by defibrillation (n = 16) and burst pacing (n = 6). The left ventricular septal and posterior endocardial surfaces were digitized immediately below the mitral valve leaflets, and indices of systolic and diastolic function were calculated. The results showed a significant impairment in both systolic and diastolic function after termination of tachyarrhythmias by defibrillation, as seen by a decrease in the shortening fraction (23.7 +/- 7.6% to 19.8 +/- 7.8%; p less than 0.005) and a decline in the peak rate of increase in left ventricular diameter during diastole called dD/dtmax (87.4 +/- 36.1 mm/sec to 71.5 +/- 28.9 mm/sec; p less than 0.01), respectively. In addition, indices of systolic and diastolic function measured at baseline were predictive of impairment in diastolic function, as seen by modest but highly significant correlations between the absolute change in dD/dtmax after defibrillation versus the peak velocity of fiber shortening (r = -0.69; p less than 0.005) and dD/dtmax (r = -0.60; p less than 0.02) measured at baseline. Left ventricular function after termination of tachyarrhythmias by burst pacing was not significantly altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of ventricular function on the exercise hemodynamics of variable rate pacing.

To determine the effect of ventricular function on the exercise hemodynamics of variable rate pacing, 16 selected patients underwent paired, double-blind, randomized exercise tests in single rate demand (VVI) or variable rate (VVIR) pacing modes. Ejection fraction and cardiac index were determined by two-dimensional and Doppler echocardiography at baseline and during peak exercise. Baseline ejection fraction ranged from 14 to 73% and was less than 40% in 6 patients (Group 1) and greater than or equal to 40% in 10 patients (Group 2). Duration of exercise was longer during the VVIR mode (502 s) than during the VVI mode (449 s) (p less than 0.01) and unrelated to baseline ejection fraction. Heart rate during exercise increased 9% in the VVI mode and 35% in the VVIR mode (p less than 0.005). Cardiac index increased 49% in the VVI mode and 83% in the VVIR mode. Analysis of variance for repeated measures showed a significant effect of pacing mode (p less than 0.01) and exercise (p less than 0.001), but not baseline ejection fraction, on cardiac index. Baseline ejection fraction did not correlate with the increase in cardiac index in either pacing mode or with the difference in increase between modes. There was no significant difference between Groups 1 and 2 in exercise duration, peak heart rate-blood pressure (rate-pressure) product, baseline or peak heart rate or baseline or peak cardiac index. Therefore, in selected patients, VVIR pacing during exercise results in an increase in heart rate, duration of exercise and cardiac index that is unrelated to the degree of baseline left ventricular dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of conduction defects on the signal-averaged electrocardiographic determination of late potentials.

To determine the effect of cardiac conduction defects on the signal-averaged electrocardiogram (ECG) and on its ability to noninvasively identify patients predisposed to ventricular tachycardia (VT), standard 12-lead ECGs and signal-averaged ECGs were obtained in 213 patients with normal conduction and 186 patients with various conduction defects. Sustained VT was induced by programmed stimulation or occurred spontaneously in 122 patients. Two-way analysis of variance showed that conduction defects and VT were associated with changes in 3 signal-averaged ECG parameters: duration of the filtered QRS, duration of the terminal QRS under 40 microV and the mean amplitude of the terminal 40 ms of the QRS. Stepwise multiple logistic regression identified 3 variables that distinguished the patient with VT with a sensitivity of 62%, a specificity of 63% and a positive predictive accuracy of 63%. These 3 variables, listed in order of importance, were conduction defect score, duration of the filtered QRS and mean amplitude of the terminal 40 ms of the QRS. These data indicate that conduction defects have systematic effects on signal-averaged ECG parameters independent of those seen in patients predisposed to VT. These effects mandate the adjustment of the definitions of late potentials in the presence of conduction defects.

A categorical course curriculum for radiology residencies.

A categorical course curriculum was introduced at Brooke Army Medical Center to focus the content of daily conferences and lectures according to radiology subspecialties. Our goal was to improve the traditional uncoordinated conferences and apprenticeship approach to resident learning. After one-year's experience, resident performance has improved, and residents and staff greatly prefer this style of teaching. The format has been adopted.

Doppler echocardiographic assessment of the effect of varying atrioventricular delay and pacemaker mode on left ventricular filling.

Pulsed Doppler echocardiography was used to study the timing and dynamics of left ventricular filling in 14 patients with permanent dual-chamber programmable pacemakers. Pacemakers were programmed to atrial sensed (VDD) mode and atrial-ventricular sequential paced mode at low (DVI-L) and high (DVI-H) heart rates, and pulsed Doppler recordings of transmitral flow were analyzed at atrioventricular delays of 50 to 300 msec in each mode. There was a significant decrease in the one-third filling fraction in both VDD and DVI-L modes and a significant increase in DVI-H modes with increasing atrioventricular delay. The ratio of early filling area to atrial filling area was significantly lower at longer atrioventricular delays in both VDD and DVI-L modes. The time from pacemaker spike to mitral valve closure was highly significantly correlated with atrioventricular delay in VDD, DVI-L, and DVI-H modes (r = -0.92, p = 0.0001; r = -0.90, p = 0.0001; and r = -0.85, p = 0.0001, respectively) as was the diastolic filling time to a lesser extent (r = -0.73, p = 0.0001; r = -0.69, p = 0.0001; r = -0.61, p = 0.0001, respectively). Events reflecting atrial systole occurred at a later time in the cardiac cycle in the atrial paced vs the atrial sensed mode. Thus changes in atrioventricular delay and pacemaker mode in this group of patients are a strong determinant of the timing and dynamics of left ventricular filling.

Utility of ambulatory electrocardiography in detecting pacemaker dysfunction in the early postimplantation period.

The value of ambulatory electrocardiography (AECG) in detecting pacemaker dysfunction before hospital discharge was assessed in 100 patients a mean of 1.2 days after pacemaker implantation. The incidence of permanent pacemaker dysfunction detected by AECG in the early postimplantation period, the frequency that pacemaker dysfunction detected by AECG was not detected by telemetric monitoring and the frequency that results of AECG led to pacemaker reprogramming before hospital discharge were determined. AECG detected at least 1 type of pacemaker dysfunction in 35% of patients and routine telemetry identified the abnormality in only 8% (p less than 0.001). Pacemaker dysfunction occurred in 42% of patients with dual-chamber devices and 27% of those with single-chamber devices (difference not significant). In the 35 patients who had pacemaker malfunction, a total of 50 instances of pacemaker dysfunction were detected. Failure of atrial capture occurred in 2% of patients, failure of atrial sensing in 9%, failure of atrial output in 1%, failure of ventricular capture in 8%, failure of ventricular sensing in 14%, failure of ventricular output due to myopotential inhibition in 11% and pacemaker-mediated tachycardia in 5%. The results of the AECG led to a clinical intervention in 22 patients (pacemaker reprogramming in 21 patients and lead repositioning in 1 patient) in whom no pacemaker dysfunction was suspected on the basis of telemetry or clinical symptoms. In conclusion, AECG provides additional benefit beyond that of routine telemetry monitoring in identifying pacemaker dysfunction in the early period after implantation.