'Relative' chemotherapy sensitivity: the impact of number of salvage regimens prior to autologous stem cell transplant for relapsed and refractory aggressive non-Hodgkin's lymphoma.

The purpose of the study was to assess the impact of number of salvage regimens needed to demonstrate chemotherapy sensitivity on relapse rates, survival, and toxicity following high-dose therapy and autologous bone marrow transplantation (ABMT) in relapsed or refractory non-Hodgkin's lymphoma. We retrospectively reviewed 136 patients with intermediate-grade lymphoma who underwent ABMT. All patients were treated with salvage therapy to maximum tumor reduction. Three quarters (102/136) of the patients received one salvage regimen, while 31 (23%) patients received two or more regimens. When compared to patients requiring >or= two regimens, patients requiring only one salvage regimen to demonstrate chemosensitivity were more likely to have a longer previous CR from initial therapy (CR >or=12 months in 47% vs 26%; P = 0.04) and to have attained CR with salvage (54% vs 16%; P = 0.001). Both median relapse-free survival (RFS) and overall survival (OS) have not yet been reached in patients receiving one salvage regimen (median follow-up 50.6 months). This is superior to the median RFS of 9.1 months (P = 0.004) and OS of 11.1 months in patients requiring >or=two regimens to demonstrate chemosensitivity (P = 0.002). Time to engraftment, toxic deaths and incidence of myelodysplasia were similar in the groups. The survival rate observed in patients requiring >or=two salvage regimens, although inferior to that of patients receiving a single salvage regimen, are still generally superior to results in the literature for patients treated with chemotherapy alone without ABMT. We conclude that high-dose therapy with ABMT is appropriate for lymphoma patients even when disease reduction requires repeated numbers of salvage regimens.

Randomized trial of peripheral blood progenitor cell vs bone marrow as hematopoietic support for high-dose chemotherapy in patients with non-Hodgkin's lymphoma and Hodgkin's disease: a clinical and molecular analysis.

Filgrastim (r-metHuG-CSF)-mobilized peripheral blood progenitor cells (PBPC) and unstimulated bone marrow (BM) were evaluated and compared for reconstitution after high-dose chemotherapy in patients with relapsed Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL) with respect to engraftment, overall and relapse-free survival, and contamination by lymphoma cells using molecular analysis of immunoglobulin gene rearrangements. Forty-four patients with either NHL or HD underwent autologous transplantation after high-dose chemotherapy. Patients were randomized to receive either Filgrastim-mobilized PBPC (n = 15) or unstimulated BM (n = 14). An additional 15 patients received PBPC without randomization because of a recent history of marrow involvement by lymphoma. Use of PBPC was associated with faster neutrophil engraftment than BM (11 vs 14 days to an absolute neutrophil count >0.5 x 10(9)/l, P = 0.04), but without any difference in platelet engraftment, infectious complications, or overall or event-free survival. Both BM (65%) and PBPC (73%) were frequently contaminated by tumor cells as assessed by CDR3 analysis. Patients with negative polymerase chain reaction analysis of a BM sample during the study had a trend towards an improved survival; however, BM involvement by disease had no impact on the ability to mobilize or collect PBPC. We conclude that PBPC are as effective as BM in reconstituting hematopoiesis after high-dose chemotherapy and that both products are frequently contaminated by sequences marking the malignant clone.

A phase II multicenter trial of high-dose sequential chemotherapy and peripheral blood stem cell transplantation as initial therapy for patients with high-risk non-Hodgkin's lymphoma.

The purpose of this study was to evaluate the safety and feasibility of front-line high-dose sequential (HDS) chemotherapy with peripheral blood stem cell (PBSC) transplantation in patients with newly diagnosed high-risk non-Hodgkin's lymphoma (NHL). Thirty-two patients with high-risk NHL (defined by the age-adjusted international index) underwent HDS chemotherapy followed by PBSC transplantation and consolidative radiotherapy. Twenty-eight patients (88%) had intermediate/high grade NHL and four patients (12%) had small noncleaved or lymphoblastic lymphoma. Twenty-four patients were classified as high-intermediate-risk (two risk factors) and eight patients were classified as high-risk (three risk factors). The five phases of HDS (see Fig. 1) consisted of Phase I (adriamycin, vincristine, and prednisone); Phase II (cyclophosphamide, filgrastim [G-CSF], and PBSC harvest); Phase III (methotrexate, leucovorin, vincristine; Phase IV (etoposide, filgrastim [G-CSF]); and Phase V (mitoxantrone, melphalan, autologous peripheral blood stem cell infusion, and filgrastim [G-CSF]). Radiation therapy was given to sites of previous bulk disease, 2400 cGy, (D + 30-100)]. Toxicity, engraftment, hospital utilization, overall survival, and relapse-free survival were evaluated. The high-dose sequential chemotherapeutic regimen was well tolerated. Treatment-related mortality was 6.25% with two deaths occurring secondary to sepsis and one death was caused by progressive disease. The major toxicity in Phase I-IV was grade 3 nausea/vomiting. The major toxicity in Phase V was grade 3 or 4 nausea/vomiting and mucositis. The median follow-up is 18.8 months (range 4-44 months). The overall survival (OS) and relapse-free survival (RFS) at 18 months for all patients were 78% (95% CI 37-90%) and 67% (95% CI 46-88%), respectively. The OS at 18 months for all patients, excluding the four patients with either small noncleaved or lymphoblastic lymphoma, was 82% (95% CI 65-98%) vs. 30% (95% CI 0-86%) (p = 0.0059). One patient in this latter group remains alive at 6 months follow-up. The RFS for all patients, excluding the four patients with either small noncleaved or lymphoblastic lymphoma, was 78% (95% CI 58-97%) vs. 0% (95% CI 0-0%) (p = 0.0004). High-dose sequential chemotherapy with initial PBSC transplantation is well tolerated and appears effective in high-risk NHL. Superior results were noted in patients with intermediate grade versus those with small noncleaved or lymphoblastic NHL.

Organic Electroluminescent Devices

Electroluminescence from organic materials has the potential to enable low-cost, full-color flat-panel displays, as well as other emissive products. Some materials have now demonstrated adequate efficiencies (1 to 15 lumens/watt) and lifetimes (>5000 hours) for practical use; however, the factors that govern lifetime remain poorly understood. This article provides a brief review of device principles and applications requirements and focuses on the understanding of reliability issues.

Repolarization current in embryonic chick atrial heart cells.

1. We have measured the delayed rectifier potassium current, IK, with the whole-cell patch-clamp technique from single cultured cells from the atria of 6- to 11-day-old chick embryonic hearts. 2. The IK component was activated with depolarizing voltage-clamp steps positive to -30 mV (holding potential in the -60 to -40 mV range). Maximum activation of the IK conductance occurred at +25 mV, based on deactivation, or tail current amplitudes upon return to the holding potential. Activation and tail current kinetics could both be described by single-exponential functions of time. 3. The IK kinetics were voltage dependent, with a maximum time constant, tau n, of approximately 2 s at V = -20 mV. 4. The IK reversal potential measurements suggest that this current is carried predominantly by potassium ions. 5. The IK results from single cells, or clusters of two or three cells, were comparable to our recent measurements of IK (IX2) in heart cell aggregates (Shrier & Clay, 1986). However, we did not obtain clear evidence in single cells for the IX1 repolarization current, in contrast to the aggregate results. 6. Computer simulations based on our IK measurements demonstrate that this component is sufficient to initiate repolarization of the action potential in single cells. However, it is not sufficient to reproduce the latter phase of repolarization for potentials negative to -30 mV. Addition of a relatively small IX1 component (2% in absolute terms compared to the aggregate work) is sufficient to account for this part of the action potential.

Enhanced evaluation of treadmill tests by means of scoring based on multivariate analysis and its clinical application: a study of 608 patients.

Six hundred eight patients being evaluated for chest pain who did not have valvular disease, cardiomyopathy, left ventricular hypertrophy or bundle branch block, and were not receiving digitalis, had treadmill tests and coronary angiograms. In 351, various exercise variables were correlated by multivariate analysis to coronary artery disease (CAD). In men, significant variables were: (1) maximal heart rate achieved less than 80% of maximal predicted heart rate (Mx PHR), (2) ST-T change greater than or equal to 1 mm, (3) age greater than or equal to 55 years and (4) treadmill time (TT) less than 8 minutes. These variables rated diagnostic scores of 9, 6, 5, and 3, respectively. A score of greater than or equal to 7 was considered diagnostic of CAD. In a test group of 192 men in which ST-T change was compared with treadmill score, sensitivity was 65 versus 85%, specificity 79 versus 74% and accuracy 69 versus 83%. In women, maximal heart rate less than 90% of Mx PHR and TT of less than 6 minutes were significant, with an accuracy of 75%. Moreover, 89% of incomplete tests and 70% of tests in patients with previous myocardial infarction were also correctly diagnosed. This method allows convenient use of significant exercise variables for clinical purposes with improved results.

A quantitative relationship of electrocardiographic criteria of left ventricular hypertrophy with echocardiographic left ventricular mass: a multivariate approach.

The purpose of this study was to evaluate the sensitivity of various electrocardiographic (EKG) criteria of left ventricular hypertrophy (LVH) in relation to echocardiographic left ventricular mass (LVME) and to assess the relative strength of various EKG variables used in the diagnosis of LVH by multivariate analysis. An attempt was also made to determine if a new combination of precordial and T-wave voltage could improve the sensitivity of EKG. In 89 patients, M-mode echocardiograms and standard EKGs were studied. Correlation of Romhilt-Estes point-score system with LVME was r = 0.621, sensitivity and specificity was 57 and 81%, respectively. Other voltage criteria had lower sensitivity. Various combinations of precordial and T-wave voltage were not superior. The quantitative relationship of individual EKG variable, QRS duration, S V1-3, R V4-6, strain T wave, left atrial abnormality, intrinsicoid deflection and axis, with LVM was, r = 0.661, 0.595, 0.429, 0.42, 0.347, and 0.225, respectively. By multivariate analysis, QRS duration, S V1-3, T-wave and R V4-6 voltage had F-value (relative strength) of 27.95, 27.15, 22.02, and 4.03, respectively, other variables were statistically insignificant. In conclusion, the most important EKG variables predictive of LVH are QRS duration, S V1-3, strain T-wave and lateral voltage in decreasing value. Rescoring these variables in accordance to their correlation to LVM may improve EKG sensitivity for the diagnosis of LVH.

Direct measurement of left ventricular ejection time from echocardiographic posterior wall excursion time: validation of technique.

Echocardiography has proven useful in determining systolic time intervals. Left ventricular mean velocity of circumferential fiber shortening has been calculated utilizing the left ventricular ejection time measured in several manners, usually from the echocardiographic aortic valve opening time or indirect carotid pulse tracing. Left ventricular ejection time is related to the time of posterior wall excursion in patients without conduction defects or segmental wall motion abnormalities. Thus, a single echocardiographic view can measure ventricular diameters and approximate ejection time simultaneously without other echocardiographic or phonocardiographic measurements which may be cumbersome to obtain, particularly during dynamic echocardiographic studies.

Use of survival analysis to determine the clinical significance of new Q waves after coronary bypass surgery.

There are few data on the long-term effects of new Q waves on survival and morbidity after coronary bypass graft surgery (CABG). We followed 1340 patients who underwent CABG in 1978 at 10 hospitals participating in the Coronary Artery Surgery Study (CASS). The incidence of perioperative Q-wave infarction was 4.76% (range 0.0-10.3% by hospital). The rate of infarction was higher in patients who had an increased left ventricular end-diastolic pressure or cardiomegaly on the preoperative chest radiograph. Patients who received more grafts or who had longer cardiopulmonary bypass time were also at higher risk of infarction. In a stepwise discriminant analysis of 44 clinical, angiographic and surgical variables, cardiopulmonary bypass time, topical cardiac hypothermia and cardiomegaly entered the stepwise selection of variables. Long-term survival was adversely affected by the appearance of new postoperative Q waves. The hospital mortality was 9.7% in the 62 patients who had new postoperative Q waves and 1.0% in the 1278 patients who did not (p less than 0.001); the 3-year cumulative survival rates were 85% and 95%, respectively (p less than 0.001). In patients who survived to hospital discharge, the presence of new postoperative Q waves did not adversely affect 3-year survival (94% and 96%, respectively). The survival rates were worse in patients who had a history of infarction or who had impaired left ventricular function preoperatively. The number of readmissions to hospital after CABG among the patients who had a transmural perioperative infarction was similar to to that among patients who did not. We conclude that the appearance of new Q waves after CABG adversely affects survival. The major impact on mortality occurs before hospital discharge. Patients who are destined to have a perioperative infarct cannot be predicted from commonly measured preoperative and angiographic variables.

Limited exercise testing soon after myocardial infarction. Correlation with early coronary and left ventricular angiography.

Forty-eight patients within 3 weeks of myocardial infarction underwent both limited treadmill graded exercise testing and coronary and left ventricular angiography. Nineteen (90%) of 21 patients with positive exercise tests (greater than or equal to 1 mm ST depression, angina, or both) had multivessel coronary artery disease. In the 27 patients with negative exercise test results, 15 (55%) had multivessel disease, 11 (41%) had single-vessel disease, and one (4%) had no coronary stenosis. Exercise-induced ST segment elevation occurred in 24 patients and predicted a significantly lower ejection fraction and higher angiographic abnormally contracting segment size. Patients experiencing angina during or after exercise had a significantly shorter 2-year survival (54% +/- 21%) than patients without exercise-induced angina (97% +/- 3%) (p less than 0.03). Thus limited exercise testing postinfarction is useful in evaluating the presence of multivessel coronary artery disease and left ventricular dysfunction and predicting long-term survival.

Interventricular septal thickness and left ventricular hypertrophy. An echocardiographic study.

Septal and left ventricular posterior wall (LVPW) thicknesses and their ratios were studied at the left ventricular outflow tract and left ventricular cavity in 66 patients with echocardiographically diagnosed left ventricular concentric hypertrophy, 20 with idiopathic hypertrophic subaortic stenosis (IHSS), and 34 normal subjects. Concentric hypertrophy was due to hypertension in 41 subjects and to valvular disease in 15 subjects. Septal thickness in normal subjects was related to body surface area (p less than 0.02). In 12% of normal subjects, 39% of patients with concentric hypertrophy and 95% with IHSS, the septal/LVPW ratio was greater than or equal to 1.3. Thirty-two percent of patients with hypertension, 78% with aortic stenosis, and 60% with aortic insufficiency had septal/LVPW ratios greater than or equal to 1.3 at left ventricular midcavity level. In conclusion, a septal/LVPW thickness ratio of greater than or equal to 1.3 is common in patients with concentric left ventricular hypertrophy and may also occur in normal subjects. A ratio greater than or equal to 1.5 may be more specific for genetically determined asymmetric septal hypertrophy.

The echocardiogram after pericardiectomy.

Many factors may affect the interventricular septal motion. This study measures the effect of pericardiectomy on septal motion in 9 patients who were evaluated 1 week to 58 months after pericardiectomy. Echocardiography was performed with the patient in recumbent position with the special care to record motion of the muscular septum and not that of the aorta. No patient had left bundle branch block, angina, myocardial infarction, pericardial effusion or right ventricular volume overload. Septal motion was paradoxical in 7, normal in 1 and could not be evaluated 1 patient. The mean value of the right ventricular internal dimension was normal. Two of 9 patients had technically satisfactory echocardiograms preoperatively. Septal motion was normal in both, and both developed paradoxical septal motion postoperatively. We conclude that paradoxical septal motion pericardiectomy, but in contrast with other causes of this finding right ventricular internal dimension remains normal.