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Background: Little is known about survival and quality of life (QoL) of patients treated by transcatheter aortic valve implantation (TAVI) compared to the age- and sex-matched general population. In this study we compared subgroups of the National Heart Registration TAVI cohort to the Dutch age- and sex-matched population at the level of survival and QoL., Methods and Results: From the Netherlands Heart Registration (NHR) the TAVI cohort (5489 patients, period 2013-2017) was extracted. These data were compared to the national Dutch population data collected from the national statistics office, Statistics Netherlands (CBS). Subgroups were defined according to sex and age (<65, 65-80 and >80). For QoL analyses the age subgroups <65, 65-75 and >75 were used. Long term survival was significantly higher in the general population compared to the TAVI population. Elderly TAVI patients (>80 years) had the same survival as the age-matched general population (46vs43% at 5 years, respectively). Survival in women was better than in men in both the general population and the TAVI cohort. Patients treated by TAVI, aged 65 years and older had a comparable QoL to that of the general population., Conclusions: This study shows that TAVI patients aged 80 years and older have a similar long-term survival as an age-matched general population. However, because of lower survival in under 80 TAVI patients, the overall long term survival of all TAVI patients is worse than that of the general population in the Netherlands. This study also suggests that QoL after TAVI treatment is comparable to QoL in the general population., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors. Published by Elsevier B.V.)

Background: Loss of high-molecular-weight multimers (HMWMs) of von Willebrand factor (vWF) occurs due to high shear stress in patients with aortic stenosis. As symptoms of aortic stenosis occur during exercise, measurement of vWF during exercise might identify patients with aortic stenosis of clinical importance. The aim of this pilot study is to evaluate whether vWF changes over time as a result of exercise in patients with asymptomatic moderate or severe aortic stenosis., Methods: Ten subjects were analysed for changes in vWF by measuring HMWMs and closure time with adenosine diphosphate (CT-ADP). All subjects underwent a full stress test on a bicycle ergometer. At rest and at peak exercise, a transthoracic echocardiogram was performed. HMWMs and CT-ADP were assessed at baseline, during and after exercise., Results: HMWMs and CT-ADP did not change significantly during exercise, p=0.45 and p=0.65, respectively. HMWMs and CT-ADP correlated well, Spearman's rho -0.621, p<0.001. HMWMs during peak exercise did not correlate with maximal velocity measured, p=0.21. CT-ADP during exercise correlated well with the maximal echocardiographic velocity over the aortic valve (AV), rho 0.82, p=0.04., Conclusions: In a cohort of 10 patients with moderate or severe aortic stenosis, we observed no significant change in vWF biomarkers during exercise. Peak CT-ADP during exercise showed a good correlation with peak AV velocity measured with echo. Although CT-ADP is an easy test to perform and could be an alternative for peak AV velocity measured during exercise, our results suggest that it can only detect large changes in shear stress., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study aimed to prospectively investigate intra-aortic balloon pump counterpulsation (IABP) support in large myocardial infarction complicated by persistent ischemia after primary percutaneous coronary intervention (PCI)., Background: Use of IABP is suggested to be effective by increasing diastolic aortic pressure, thereby improving coronary blood flow. This can only be expected with exhausted coronary autoregulation, typical in acute myocardial infarction complicated by persistent ischemia. In this situation, augmented diastolic pressure is expected to increase myocardial oxygenation., Methods: One hundred patients with large STEMI complicated by persistent ischemia after primary PCI were randomized to treatment with or without IABP therapy on top of standard care. IABP support was initiated following primary PCI, immediately after inclusion. Primary end point was all-cause mortality, need for (additional) mechanical hemodynamic support, or readmission for heart failure within 6 months., Results: Mean age was 63 ± 10 years, 76% were male. Mean systolic and diastolic blood pressure were 120 ± 25 mmHg and 73 ± 17 mmHg. Mean heart rate was 75 ± 18 mmHg. Before PCI, mean summed ST-deviation was 21 ± 8 mm with only minimal ST-resolution after PCI. One patient in the IABP group reached the primary end point versus four patients in the control group (2% vs. 8%; p = 0.16). After primary PCI, resolution of ST-deviation was significantly more pronounced in the IABP group (73 ± 17%) compared to the control group (56 ± 26%; p < 0.01)., Conclusions: In this pilot study, in patients with large STEMI and persistent ischemia after primary PCI, use of IABP showed a nonsignificant decrease in mortality, necessity for (additional) mechanical hemodynamic support or readmission for heart failure at 6 months, and resulted in more rapid ST-resolution., (© 2019 Wiley Periodicals, Inc.)

Background: Diffuse atherosclerosis is commonly observed in angiographically normal segments in patients with stable coronary artery disease (CAD). The distribution of epicardial resistance along the vessel can be evaluated using coronary physiology., Objectives: The purpose of this study was to characterize the pathophysiological patterns of CAD using invasive pressure pullbacks during continuous hyperemia., Methods: In this prospective, multicenter study of patients undergoing clinically-indicated coronary angiography due to stable angina, a pressure-wire pullback device was set at a speed of 1 mm/s. Based on coronary angiography and on the fractional flow reserve (FFR) pullback curve, the patterns of CAD were adjudicated as focal, diffuse, or a combination of both. The distribution of epicardial resistance was characterized using the hyperemic pullback pressure gradients (PPGs). The PPG index, a continuous metric based on the magnitude of pressure drop over 20 mm and on the extent of functional disease was computed to determine the pattern of CAD. Low PPG index indicates diffuse CAD., Results: A total of 158 vessels (n = 117) were included. Overall, 984,813 FFR values were used to generate 100 FFR pullback curves. Using coronary physiology, 36% of the vessel disease patterns were reclassified compared to angiography. The median of maximal PPG over 20 mm was 0.083 (interquartile range: 0.063 to 0.118) FFR units, and the mean extent of functional disease was 39.3 ± 21.3 mm. The mean PPG index was 0.58 ± 0.18 and differentiated pathophysiological focal and diffuse disease (p < 0.001)., Conclusions: Pathophysiological patterns of CAD can be characterized by motorized hyperemic PPGs. The evaluation of the FFR pullback curve reclassified one-third of the vessels' disease patterns compared with conventional angiography. The PPG index is a novel metric that quantifies the distribution of epicardial resistance and discriminates focal from diffuse CAD. (Physiological Patterns of Coronary Artery Disease; NCT03824600)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Abandoned leads are often linked to complications during lead extraction, prompting pre-emptive extraction if leads become non-functional. We examined their influence on complications when extracted for device-related infection., Methods and Results: All patients undergoing lead extraction for device-related infection from 2006 to 2017 in our hospital were included. The primary endpoint was major complications. Out of 500 patients, 141 had abandoned leads, of whom 75% had only one abandoned lead. Median cumulative implant times were 24.2 (interquartile range 15.6-38.2) and 11.6 (5.6-17.4), respectively years with or without abandoned leads. All leads were extracted only with a femoral approach in 50.4% of patients. Mechanical rotational tools were introduced in 2014 and used in 22.2% of cases and replacing laser sheaths that were used in 5% of patients. Major complications occurred in 0.7% of patients with abandoned leads compared with 1.7% of patients with only active leads (P = 0.679). Failure to completely remove all leads was 14.9% and 6.4%, respectively with or without abandoned leads (P = 0.003), and clinical failure was 6.4% and 2.2% (P = 0.028), respectively. Procedural failure dropped to 9.2% and 5.7% (P = 0.37), respectively after the introduction of mechanical rotational tools. The only independent predictor of procedural and clinical failure in multivariate analysis was the cumulative implant duration., Conclusion: Despite longer implant times, patients with abandoned leads did not have more major complications during lead extraction. Therefore, preventive extraction of non-functional leads to avoid complications at a later stage is not warranted., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Hypothermia, if provided before coronary reperfusion, reduces infarct size in animal models of acute myocardial infarction (AMI). Translation to humans has failed so far, because the target temperature is not reached in time within the endangered myocardium using systemic hypothermia method. Hence, a clinically applicable method has been developed to provide intracoronary hypothermia using cold saline, selectively infused locally into the infarct area. In this study, a lumped parameter model has been designed to support the clinical method and to describe this myocardial cooling process mathematically. This model is able to predict the myocardial temperature changes over time, which cannot be measured, based on the temperature and flow of the intracoronary injected cold saline and coronary arterial blood. It was validated using data from an isolated beating porcine heart model and applied on data from patients with AMI undergoing intracoronary hypothermia. In prospect, the computational model may be used as an assistive tool to calculate the patient specific flow rate and temperature of saline required for reliable achievement of the target myocardial temperature in the hypothermia enhanced clinical treatment of AMI., (Copyright © 2019 IPEM. Published by Elsevier Ltd. All rights reserved.)

Aims: Randomised controlled trials have reported instantaneous wave-free ratio (iFR) to be non-inferior to fractional flow reserve (FFR) for major adverse cardiovascular events at one year; however, iFR is limited by sensitive landmarking of the pressure waveform, and the assumption that maximal flow and minimal resistance occur during a fixed period of diastole. We sought to validate the resting full-cycle ratio (RFR), a novel non-hyperaemic index of coronary stenosis severity based on unbiased identification of the lowest distal coronary pressure to aortic pressure ratio (Pd/Pa), independent of the ECG, landmark identification, and timing within the cardiac cycle., Methods and Results: VALIDATE-RFR was a retrospective study designed to derive and validate the RFR. The primary endpoint was the agreement between RFR and iFR. RFR was retrospectively determined in 651 waveforms in which iFR was measured using a proprietary Philips/Volcano wire. RFR was highly correlated to iFR (R2=0.99, p<0.001), with a mean bias of -0.002 (95% limits of agreement -0.023 to 0.020). The diagnostic performance of RFR versus iFR was diagnostic accuracy 97.4%, sensitivity 98.2%, specificity 96.9%, positive predictive value 94.5%, negative predictive value 99.0%, area under the receiver operating characteristic curve of 0.996, and diagnostically equivalent within 1% (mean difference -0.002; 95% CI: -0.009 to 0.006, p=0.03). The RFR was detected outside diastole in 12.2% (341/2,790) of all cardiac cycles and 32.4% (167/516) of cardiac cycles in the right coronary artery where the sensitivity of iFR compared to FFR was lowest (40.6%)., Conclusions: RFR is diagnostically equivalent to iFR but unbiased in its ability to detect the lowest Pd/Pa during the full cardiac cycle, potentially unmasking physiologically significant coronary stenoses that would be missed by assessment dedicated to specific segments of the cardiac cycle.

Aims: Videodensitometric assessment of aortography provides a periprocedural quantitation of prosthetic valve regurgitation (PVR) after transcatheter aortic valve implantation. We sought to compare the videodensitometric parameters of PVR severity to the regurgitation fraction (RF) in a controlled in vitro setting., Methods and Results: In a mock circulation system, a transcatheter balloon-expandable valve inserted at the aortic valve position was gradually deformed to induce different grades of paravalvular leakage and the RF was measured with a transonic flow probe. Contrast aortography was performed and the following videodensitometric parameters were generated: left ventricle aortic regurgitation (LV-AR), LV outflow tract AR (LVOT-AR), quantitative regurgitation assessment (qRA) index, relative maximum density (relative max), and maximum upslope of the LV time-density curve. The correlation was substantial between videodensitometric parameters (LV-AR, LVOT-AR, qRA index, relative max, and maximum upslope) and RF (r2=0.96, 0.96, 0.93, 0.87, and 0.93; p<0.001 for all). LV-AR (region of interest [ROI]=entire LV) and LVOT-AR (ROI=LVOT) were not different (p=0.51) and were strongly correlated (r2=0.99) with a mean difference of 1.92% (95% limits of agreement: ±2.83). The correlations of LV-AR and LVOT-AR with RF were stronger when more than one cardiac cycle was included in the analysis (one cycle: r2=0.85 and r2=0.83; four cycles: r2=0.96 and r2=0.96, for LV-AR and LVOT-AR, respectively). Including more cycles beyond four did not improve accuracy., Conclusions: Quantitative assessment of PVR by videodensitometry of aortograms strongly correlates with the actual RF in a controlled in vitro setting. Accuracy is improved by including more than one cardiac cycle in the analysis.

Aims: In the minimalist transcatheter aortic valve implantation (TAVI) era, the usage of transoesophageal echocardiography has become restricted. Conversely, aortography has gained clinical ground in quantifying prosthetic valve regurgitation (PVR) during the procedure. In a mock circulation system, we sought to compare the contrast volume required and the accuracy of aortographic videodensitometric PVR assessment using a synchronised diastolic and standard (non-synchronised) injection aortography., Methods and Results: Synchronised diastolic injection triggered by the signal stemming from the mock circulation was compared with standard non-synchronised injection. A transcatheter heart valve was implanted and was deformed step by step by advancing a screw perpendicularly to the cage of the valve in order to create increasing PVR. Quantitative measurement of PVR was derived from time-density curves of both a reference area (aortic root) and a region of interest (left ventricle) developed by a videodensitometric software. The volume of contrast required for the synchronised diastolic injection was significantly less than in the non-synchronised injection (8.1 [7.9-8.5] ml vs. 19.4 [19.2-19.9] ml, p<0.001). The correlation between the two methods was substantial (Spearman's coefficient rho ranging from 0.991 to 0.968). Intraobserver intra-class correlation coefficient for both methods of injection was 0.999 (95% CI: 0.996-1.000) for the synchronised diastolic and 0.999 (95% CI: 0.996-1.000) for the non-synchronised injection group. The mean difference in the rating was 0.17% and limits of agreement were ±1.64% for both groups., Conclusions: A short synchronised diastolic injection enables contrast volume reduction during aortography without compromising the accuracy of the quantitative assessment of PVR using videodensitometry.

Aims: Hypothermia reduces reperfusion injury and infarct size in animal models of acute myocardial infarction if started before reperfusion. Human studies have not confirmed benefit, probably due to insufficient myocardial cooling and adverse systemic effects. This study sought to assess the safety and feasibility of a novel method for selective, sensor-monitored intracoronary hypothermia., Methods and Results: Ten patients undergoing primary percutaneous coronary intervention (PPCI) were included. Saline at room temperature was administered distal to the culprit lesion through an inflated overthe- wire balloon (OTWB) in order to cool the endangered myocardium for 10 minutes (occlusion phase). Next, the OTWB was deflated and cooling continued with saline at 4°C for another 10 minutes (reperfusion phase). A sensor-tipped temperature wire in the distal coronary artery allowed titration of the infusion rate to achieve the desired coronary temperature (6°C below body temperature). Target coronary temperature was achieved within 27 seconds (median; IQR 21-46). Except for two patients with inferior wall infarction experiencing transient conduction disturbances, no side effects occurred. Systemic temperature remained unchanged. Finally, PPCI was performed as per routine., Conclusions: Selective hypothermia of the infarct area by intracoronary infusion of saline provides a novel method to reduce coronary temperature quickly and guarantee local myocardial hypothermia. In anterior wall myocardial infarctions, the protocol appeared safe, without serious haemodynamic or systemic side effects. In inferior wall myocardial infarctions, transient conduction abnormalities of short duration occurred. Potentially, selective intracoronary delivery of hypothermia could attenuate reperfusion injury caused by traditional PPCI.

Because current reperfusion strategies in acute myocardial infarction (AMI) seem to be exhausted in terms of additional mortality benefit, there remains a need for new methods to attenuate reperfusion injury and, thereby, further reduce myocardial infarct size and improve long-term survival. Therapeutic hypothermia (32-35°C) diminishes reperfusion injury and reduces infarct size in a variety of animal models of AMI if provided before reperfusion. In human studies this reduction has not been confirmed so far, most likely because systemic cooling acts slowly, and therefore, the target temperature is not reached in time or at all in a substantial number of patients. Furthermore, systemic cooling can cause adverse effects such as severe shivering, volume overload, and an enhanced adrenergic state. In most randomized clinical trials, however, subgroups of patients with anterior myocardial infarction that reached the target temperature before reperfusion did show a reduction in infarct size. To transform therapeutic hypothermia into a clinically feasible treatment for AMI, its method must be modified. An ideal technique should be quick enough to achieve sufficient myocardial hypothermia before reperfusion, without significant delay and without the adverse effects of systemic cooling. In this review, we propose a novel, potentially feasible method of selective intracoronary hypothermia to overcome the problems encountered with prior techniques.

Aims: The aim of this study is to validate a novel monorail infusion catheter for thermodilution-based quantitative coronary flow measurements., Methods and Results: Based on the principles of thermodilution, volumetric coronary flow can be determined from the flow rate of a continuous saline infusion, the temperature of saline when it enters the coronary artery, and the temperature of the blood mixed with the saline in the distal part of the coronary artery. In an in vitro set-up of the systemic and coronary circulation at body temperature, coronary flow values were varied from 50-300 ml/min in steps of 50 ml/min. At each coronary flow value, thermodilution-based measurements were performed at infusion rates of 15, 20, and 30 ml/min. Temperatures and pressures were simultaneously measured with a pressure/temperature sensor-tipped guidewire. Agreement of the calculated flow and the measured flow as well as repeatability were assessed. A total of five catheters were tested, with a total of 180 measurements. A strong correlation (ρ=0.976, p<0.0001) and a difference of -6.5±15.5 ml/min were found between measured and calculated flow. The difference between two repeated measures was 0.2%±8.0%., Conclusions: This novel infusion catheter used in combination with a pressure/temperature sensor-tipped guidewire allows accurate and repeatable absolute coronary flow measurements. This opens a window to a better understanding of the coronary microcirculation.

Background/purpose: In a number of patients with acute myocardial infarction (AMI), myocardial hypoperfusion, known as the no-reflow phenomenon, persists after primary percutaneous intervention (PPCI). The aim of this study was to evaluate the feasibility and safety of a new quantitative method of measuring absolute blood flow and resistance within the perfusion bed of an infarct-related artery. Furthermore, we sought to study no-reflow by correlating these measurements to the index of microvascular resistance (IMR) and the area at risk (AR) as determined by cardiac magnetic resonance imaging (CMR)., Methods: Measurements of absolute flow and myocardial resistance were performed in 20 patients with ST-segment elevation myocardial infarction (STEMI), first immediately following PPCI and then again after 3-5days. These measurements used the technique of thermodilution during a continuous infusion of saline. Flow was expressed in ml/min per gram of tissue within the area at risk., Results: The average time needed for measurement of absolute flow, resistance and IMR was 20min, and all measurements could be performed without complication. A higher flow supplying the AR correlated with a lower IMR in the acute phase. Absolute flow increased from 3.14 to 3.68ml/min/g (p=0.25) and absolute resistance decreased from 1317 to 1099 dyne.sec.cm-5/g (p=0.40) between the first day and fifth day after STEMI., Conclusions: Measurement of absolute flow and microvascular resistance is safe and feasible in STEMI patients and may allow for a better understanding of microvascular (dys)function in the early phase of AMI., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: The aim of this study was to compare the hyperaemic effect of a single bolus regadenoson injection to a central venous adenosine infusion for inducing hyperaemia in the measurement of fractional flow reserve (FFR)., Methods and Results: One hundred patients scheduled for FFR measurement were enrolled. FFR was first measured by IV adenosine (140 µg/kg/min), thereafter by IV bolus regadenoson injection (400 µg), followed by another measurement by IV adenosine and bolus injection of regadenoson. The regadenoson injections were randomised to central or peripheral intravenous. Hyperaemic response and duration of steady state maximum hyperaemia were studied, central versus peripheral venous regadenoson injections were compared, and safety and reproducibility of repeated injections were investigated. Mean age was 66±8 years, 75% of the patients were male. The target stenosis was located in the LM, LAD, LCX, and RCA in 7%, 54%, 20% and 19%, respectively. There was no difference in FFR measured by adenosine or by regadenoson (ΔFFR=0.00±0.01, r=0.994, p<0.001). Duration of maximum hyperaemia after regadenoson was variable (10-600 s). No serious side effects of either drug were observed., Conclusions: Maximum coronary hyperaemia can be achieved easily, rapidly, and safely by one single intravenous bolus of regadenoson administered either centrally or peripherally. Repeated regadenoson injections are safe. The hyperaemic plateau is variable. Clinical Trial Registration: http://clinicaltrials.gov/ct2/ show/study/NCT01809743?term=NCT01809743&rank=1 (ClinicalTrials.gov Identifier: NCT01809743).

The blood pressure changes induced by the intra-aortic balloon pump (IABP) are expected to create clinical improvement in terms of coronary perfusion and myocardial oxygen consumption. However, the measured effects reported in literature are inconsistent. The aim of this study was to investigate the influence of ischemia on IABP efficacy in healthy hearts and in shock. Twelve slaughterhouse porcine hearts (hearts 1-12) were connected to an external circulatory system, while physiologic cardiac performance was restored. Different clinical scenarios, ranging from healthy to cardiogenic shock, were simulated by step-wise administration of negative inotropic drugs. In hearts 7-12, severe global myocardial ischemia superimposed upon the decreased contractile states was created. IABP support was applied in all hearts under all conditions. Without ischemia, the IABP induced a mild increase in coronary blood flow and cardiac output. These effects were strongly augmented in the presence of persisting ischemia, where coronary blood flow increased by 49 ± 24% (P < 0.01) and cardiac output by 17 ± 6% (P < 0.01) in case of severe pump failure. As expected, myocardial oxygen consumption increased in case of ischemia (21 ± 17%; P < 0.01), while it slightly decreased without (-3 ± 6%; P < 0.01). In case of progressive pump failure due to persistent myocardial ischemia, the IABP increased hyperemic coronary blood flow and cardiac output significantly, and reversed the progressive hemodynamic deterioration within minutes. This suggests that IABP therapy in acute myocardial infarction is most effective in patients with viable myocardium, suffering from persistent myocardial ischemia, despite adequate epicardial reperfusion., (Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Aims: This substudy investigated IABP support in large STEMI complicated by persistent ischaemia within the original CRISP-AMI trial., Methods and Results: Patients were included if the ECG at admission showed summed ST deviation (ST-D) ≥15 mm and the ECG post PCI showed poor ST resolution (<50%). Endpoints evaluated were all-cause mortality at six months and the composite endpoint of death, cardiogenic shock or new or worsening heart failure at six months. One hundred and forty-nine patients had ST-D ≥15 mm (mean ST-D 24±8 mm). Of these patients, 36 (24%) showed poor ST resolution (15 patients in the IABP group; 21 patients in the control group). Mean age was 55±11 years, 89% were male. Mean systolic and diastolic blood pressures were 135±31 mmHg and 83±22 mmHg, respectively. The left anterior descending coronary artery was the infarct-related artery in all cases, primary PCI was successful in 94%. At six months, zero patients in the IABP group died versus five patients in the control group (0% versus 24%; p=0.046). There was a trend towards statistical significance in the composite endpoint (one patient [7%] versus seven patients [33%]; p=0.06)., Conclusions: In this substudy, use of IABP was associated with decreased six-month mortality in large STEMI complicated by persistent ischaemia after PCI.

Objectives: This study sought to examine the diagnostic accuracy of the instantaneous wave-free ratio (iFR) and resting distal coronary artery pressure/aortic pressure (Pd/Pa) with respect to hyperemic fractional flow reserve (FFR) in a core laboratory-based multicenter collaborative study., Background: FFR is an index of the severity of coronary stenosis that has been clinically validated in 3 prospective randomized trials. iFR and Pd/Pa are nonhyperemic pressure-derived indices of the severity of stenosis with discordant reports regarding their accuracy with respect to FFR., Methods: iFR, resting Pd/Pa, and FFR were measured in 1,768 patients from 15 clinical sites. An independent physiology core laboratory performed blinded off-line analysis of all raw data. The primary objectives were to determine specific iFR and Pd/Pa thresholds with ≥90% accuracy in predicting ischemic versus nonischemic FFR (on the basis of an FFR cut point of 0.80) and the proportion of patients falling beyond those thresholds., Results: Of 1,974 submitted lesions, 381 (19.3%) were excluded because of suboptimal acquisition, leaving 1,593 for final analysis. On receiver-operating characteristic analysis, the optimal iFR cut point for FFR ≤0.80 was 0.90 (C statistic: 0.81 [95% confidence interval: 0.79 to 0.83]; overall accuracy: 80.4%) and for Pd/Pa was 0.92 (C statistic: 0.82 [95% confidence interval: 0.80 to 0.84]; overall accuracy: 81.5%), with no significant difference between these resting measures. iFR and Pd/Pa had ≥90% accuracy to predict a positive or negative FFR in 64.9% (62.6% to 67.3%) and 48.3% (45.6% to 50.5%) of lesions, respectively., Conclusions: This comprehensive core laboratory analysis comparing iFR and Pd/Pa with FFR demonstrated an overall accuracy of ~80% for both nonhyperemic indices, which can be improved to ≥90% in a subset of lesions. Clinical outcome studies are required to determine whether the use of iFR or Pd/Pa might obviate the need for hyperemia in selected patients., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The oxygen uptake efficiency slope (OUES) is an exercise parameter with strong prognostic value in the heart failure population. Yet, the optimal determination method of OUES remains unclear. The purpose of the present study was to investigate the influence of the ventilatory anaerobic threshold (VAT) and occurrence of a plateau in oxygen uptake (VO2) on determination of OUES from submaximal exercise data in patients with chronic heart failure (CHF)., Methods and Results: Ninety-eight CHF patients (New York Heart Association class II-III) were included. All patients performed a symptom-limited exercise test with gas exchange analysis on a cycle ergometer. VAT was determined by the V-slope method and OUES was derived via least-squares linear regression using 100% (OUES100), 90% (OUES90), and 75% (OUES75) of exercise duration, and, in addition, by using only the first 50% of data points preceding VAT (OUES½VAT), all data preceding VAT (OUESVAT), and only data following VAT (OUESpostVAT). Whereas OUESVAT (1720 ± 430 ml/min/log(l/min)), OUES75 (1811 ± 476 ml/min/log(l/min)), and OUESpostVAT (1742 ± 564 ml/min/log(l/min)) were not significantly different from OUES100 (1767 ± 542 ml/min/log(l/min)), OUES½VAT (1500 ± 314 ml/min/log(l/min)) was significantly lower than all other values (p < 0.01). When a VO2 plateau was present, OUES100 was lower than OUES90 (p < 0.05)., Conclusions: The study results indicate that OUES values should be interpreted with caution when CHF patients do not reach the ventilatory anaerobic threshold or when a VO2 plateau is present.

Background: Previous studies on gender differences in outcome in patients with ST segment elevation myocardial infarction (STEMI) have been performed, but most of those are from before the current era of PCI technique and medical therapy and have a short duration of follow-up. The objective of our study is to assess the influence of gender on long-term outcome in patients with STEMI who underwent primary percutaneous intervention (PCI) between January 2006 and May 2008., Methods: Two-year follow-up data from 202 female and 668 male patients undergoing primary PCI for STEMI were available from the DEBATER (A Comparison of Drug Eluting and Bare Metal Stents for Primary Percutaneous Coronary Intervention with or without Abciximab in ST-segment elevation Myocardial Infarction: The Eindhoven Reperfusion Study) trial database. The primary endpoint was major adverse cardiac events (MACE), defined as the composite of death, myocardial infarction, and target vessel revascularization., Results: Women were older (64.7 ± 11.7 vs. 59.0 ± 10.7; P < 0.001), and had more often diabetes mellitus (15% vs. 9%; P = 0.01) and hypertension (44% vs. 25%; P < 0.001). At two years, the rate of MACE was significantly higher in women (21% vs. 14%; P = 0.02). The mortality rate in women was 8% versus 2.6% in men (P < 0.001). However, multivariate analysis after adjustment for age and the baseline characteristics hypertension, smoking, diabetes mellitus, stent diameter, and time between onset of symptoms and arrival of the ambulance showed similar MACE and mortality rates in men and women., Conclusion: Women have higher rates of both MACE and mortality after primary PCI for STEMI compared to men because of higher age with higher baseline risk profiles., (Copyright © 2013 Wiley Periodicals, Inc.)

The isolated beating pig heart model is an accessible platform to investigate the coronary circulation in its truly morphological and physiological state, whereas its use is beneficial from a time, cost, and ethical perspective. However, whether the coronary autoregulation is still intact is not known. Here, we study the autoregulation of coronary blood flow in the working isolated pig heart in response to brief occlusions of the coronary artery, to step-wise changes in left ventricular loading conditions and contractile states, and to pharmacologic vasodilating stimuli. Six slaughterhouse pig hearts (473 ± 40 g) were isolated, prepared, and connected to an external circulatory system. Through coronary reperfusion and controlled cardiac loading, physiological cardiac performance was achieved. After release of a coronary occlusion, coronary blood flow rose rapidly to an equal (maximum) level as the flow during control beats, independent of the duration of occlusion. Moreover, a linear relation was found between coronary blood flow and coronary driving pressure for a wide variation of preload, afterload, and contractility. In addition, intracoronary administration of papaverine did not yield a transient increase in blood flow indicating the presence of maximum coronary hyperemia. Together, this indicates that the coronary circulation in the isolated beating pig heart is in a permanent state of maximum hyperemia. This makes the model excellently suitable for testing and validating cardiovascular devices (i.e., heart valves, stent grafts, and ventricular assist devices) under well-controlled circumstances, whereas it decreases the necessity of sacrificing large mammalians for performing classical animal experiments., (© 2013, Copyright the Authors. Artificial Organs © 2013 Wiley Periodicals, Inc. and International Center for Artificial Organs and Transplantation.)

Objectives: This study sought to examine the clinical performance of and theoretical basis for the instantaneous wave-free ratio (iFR) approximation to the fractional flow reserve (FFR)., Background: Recent work has proposed iFR as a vasodilation-free alternative to FFR for making mechanical revascularization decisions. Its fundamental basis is the assumption that diastolic resting myocardial resistance equals mean hyperemic resistance., Methods: Pressure-only and combined pressure-flow clinical data from several centers were studied both empirically and by using pressure-flow physiology. A Monte Carlo simulation was performed by repeatedly selecting random parameters as if drawing from a cohort of hypothetical patients, using the reported ranges of these physiologic variables., Results: We aggregated observations of 1,129 patients, including 120 with combined pressure-flow data. Separately, we performed 1,000 Monte Carlo simulations. Clinical data showed that iFR was +0.09 higher than FFR on average, with ±0.17 limits of agreement. Diastolic resting resistance was 2.5 ± 1.0 times higher than mean hyperemic resistance in patients. Without invoking wave mechanics, classic pressure-flow physiology explained clinical observations well, with a coefficient of determination of >0.9. Nearly identical scatter of iFR versus FFR was seen between simulation and patient observations, thereby supporting our model., Conclusions: iFR provides both a biased estimate of FFR, on average, and an uncertain estimate of FFR in individual cases. Diastolic resting myocardial resistance does not equal mean hyperemic resistance, thereby contravening the most basic condition on which iFR depends. Fundamental relationships of coronary pressure and flow explain the iFR approximation without invoking wave mechanics., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Because of the large number of interaction factors involved, the effects of the intra-aortic balloon pump (IABP) have not been investigated deeply. To enhance its clinical efficiency and to better define indications for use, advanced models are required to test the interaction between the IABP and the cardiovascular system. A patient with mild blood pressure depression and a lowered cardiac output is modeled in a lumped parameter computational model, developed with physiologically representative elements for relevant components of circulation and device. IABP support is applied, and the moments of balloon inflation and deflation are varied around their conventional timing modes. For validation purposes, timing is adapted within acceptable ranges in ten patients undergoing IABP therapy for typical clinical indications. In both model and patients, the IABP induces a diastolic blood pressure augmentation as well as a systolic reduction in afterload. The support capabilities of the IABP benefit the most when the balloon is deflated simultaneously with ventricular contraction, whereas inflation before onset of diastole unconditionally interferes with ejection. The physiologic response makes the model an excellent tool for testing the interaction between the IABP and the cardiovascular system, and how alterations of specific IABP parameters (i.e., timing) affect this coupling.

Background: New-generation high-sensitivity assays for cardiac troponin have lower detection limits and less imprecision than earlier assays. Reference 99th-percentile cutoff values for these new assays are also lower, leading to higher frequencies of positive test results. When cardiac troponin concentrations are minimally increased, serial testing allows discrimination of myocardial infarction from other causes of increased cardiac troponin. We assessed various measures of short-term variation, including absolute concentration changes, reference change values (RCVs), and indices of individuality (II) for 2 cardiac troponin assays in emergency department (ED) patients., Methods: We collected blood from patients presenting with cardiac chest pain upon arrival in the ED and 2, 6, and 12 h later. Cardiac troponin was measured with the high-sensitivity cardiac troponin T (hs-cTnT) assay (Roche Diagnostics) and a sensitive cTnI assay (Siemens Diagnostics). Cardiac troponin results from 67 patients without acute coronary syndrome or stable angina were used in calculating absolute changes in cardiac troponin, RCVs, and II., Results: The 95th percentiles for absolute change in cardiac troponin were 8.3 ng/L for hs-cTnT and 28 ng/L for cTnI. Within-individual and total CVs were 11% and 14% for hs-cTnT and 18% and 21% for cTnI, respectively. RCVs were 38% (hs-cTnT) and 57% (cTnI). The corresponding log-normal RCVs were +46%/-32% for hs-cTnT and +76%/-43% for cTnI. II values were 0.31 (cTnI) and 0.12 (hs-cTnT)., Conclusions: The short-term variations and IIs of cardiac troponin were low in ED patients free of ischemic myocardial necrosis. The detection of cardiac troponin variation exceeding reference thresholds can help to identify ED patients with acute myocardial necrosis whereas variation within these limits renders acute coronary syndrome unlikely.

Objectives: The goal of this study was to demonstrate superiority of sirolimus-eluting stents (SES) over bare-metal stents (BMS) and of abciximab over no abciximab in primary percutaneous coronary intervention (PCI)., Background: Drug-eluting stents (DES) are increasingly used in primary PCI, but the recommendations for use in primary PCI are based on a few randomized controlled trials with selected patients. The usefulness of abciximab in primary PCI is not established., Methods: Nine hundred seven patients referred to the Catharina Hospital were randomized to SES or BMS, and to abciximab or no abciximab in a prospective, randomized, open 2 × 2 factorial trial with blinded evaluation. Primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), defined as the composite of death, myocardial infarction (MI), stroke, repeat revascularization, and bleeding at 1 year (stent arm) and the composite of death, target vessel MI, target vessel revascularization (TVR), and bleeding at 30 days (abciximab arm)., Results: At 1 year, the rate of MACCE was lower in the SES arm (16.5% vs. 25.8%, p = 0.001), mainly driven by less repeat revascularization (9.8% vs. 16.8%; p = 0.003) and without influencing the cumulative incidence of death and MI (5.2% vs. 5.8%; p = 0.68). At 30 days, the rate of the composite of death, target vessel MI, TVR, and bleeding was lower in the abciximab arm (8.2% vs. 12.4%, p = 0.04), mainly driven by less TVR due to less stent thrombosis (1.2% vs.7.4%, p < 0.001). However, bleeding complications occurred more frequently in the abciximab group (5.7% vs. 2.8%, p = 0.03)., Conclusions: Primary PCI with SES reduces adverse events at 1 year, mainly by reduction of repeat revascularization, whereas abciximab reduces early stent thrombosis, at the expense of more bleeding complications. (Comparison of Drug Eluting and Bare Metal Stents With or Without Abciximab in ST Elevation Myocardial Infarction [DEBATER]; NCT00986050)., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: In 2006, we published the results of the European Organisation for Research and Treatment of Cancer phase III trial EORTC 20981 on the role of rituximab in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). At that time, the median follow-up for the maintenance phase was 33 months. Now, we report the long-term outcome of maintenance treatment, with a median follow-up of 6 years., Patients and Methods: Overall, 465 patients were randomly assigned to induction with either six cycles of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab plus CHOP (R-CHOP). Those in complete remission or partial remission after induction (n = 334) were randomly assigned to maintenance treatment with rituximab (375 mg/m(2) intravenously once every 3 months) or observation., Results: Rituximab maintenance significantly improved progression-free survival (PFS) compared with observation (median, 3.7 years v 1.3 years; P < .001; hazard ratio [HR], 0.55), both after CHOP induction (P < .001; HR, 0.37) and R-CHOP (P = .003; HR, 0.69). The 5-year overall survival (OS) was 74% in the rituximab maintenance arm, and it was 64% in the observation arm (P = .07). After progression, a rituximab-containing salvage therapy was given to 59% of patients treated with CHOP followed by observation, compared with 26% after R-CHOP followed by rituximab maintenance. Rituximab maintenance was associated with a significant increase in grades 3 to 4 infections: 9.7% v 2.4% (P = .01)., Conclusion: With long-term follow-up, we confirm the superior PFS with rituximab maintenance in relapsed/resistant FL. The improvement of OS did not reach statistical significance, possibly because of the unbalanced use of rituximab in post-protocol salvage treatment.

Background: In patients with multivessel coronary artery disease who are undergoing percutaneous coronary intervention (PCI), coronary angiography is the standard method for guiding the placement of the stent. It is unclear whether routine measurement of fractional flow reserve (FFR; the ratio of maximal blood flow in a stenotic artery to normal maximal flow), in addition to angiography, improves outcomes., Methods: In 20 medical centers in the United States and Europe, we randomly assigned 1005 patients with multivessel coronary artery disease to undergo PCI with implantation of drug-eluting stents guided by angiography alone or guided by FFR measurements in addition to angiography. Before randomization, lesions requiring PCI were identified on the basis of their angiographic appearance. Patients assigned to angiography-guided PCI underwent stenting of all indicated lesions, whereas those assigned to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was 0.80 or less. The primary end point was the rate of death, nonfatal myocardial infarction, and repeat revascularization at 1 year., Results: The mean (+/-SD) number of indicated lesions per patient was 2.7+/-0.9 in the angiography group and 2.8+/-1.0 in the FFR group (P=0.34). The number of stents used per patient was 2.7+/-1.2 and 1.9+/-1.3, respectively (P<0.001). The 1-year event rate was 18.3% (91 patients) in the angiography group and 13.2% (67 patients) in the FFR group (P=0.02). Seventy-eight percent of the patients in the angiography group were free from angina at 1 year, as compared with 81% of patients in the FFR group (P=0.20)., Conclusions: Routine measurement of FFR in patients with multivessel coronary artery disease who are undergoing PCI with drug-eluting stents significantly reduces the rate of the composite end point of death, nonfatal myocardial infarction, and repeat revascularization at 1 year. (ClinicalTrials.gov number, NCT00267774.), (2009 Massachusetts Medical Society)

Background: Abdominal aortic aneurysms (AAA) are at risk of rupture when the internal load (blood pressure) exceeds the aneurysm wall strength. Generally, the maximal diameter of the aneurysm is used as a predictor of rupture; however, biomechanical properties may be a better predictor than the maximal diameter. Compliance and distensibility are two biomechanical properties that can be determined from the pressure-volume relationship of the aneurysm. This study determined the compliance and distensibility of the AAA by simultaneous instantaneous pressure and volume measurements; as a secondary goal, the influence of direct and indirect pressure measurements was compared., Methods: Ten men (aged 73.6 +/- 6.4 years) with an infrarenal AAA were studied. Three-dimensional balanced turbo field echo (3D B-TFE) images were acquired with noncontrast-enhanced magnetic resonance imaging (MRI) for the aortic region proximal to the renal arteries until just beyond the bifurcation. Volume changes were extracted from the electrocardiogram-triggered 3D B-TFE MRI images using dedicated prototype software. Pressure was measured simultaneously within the AAA using a fluid-filled pigtail catheter. Noninvasive brachial cuff measurements were also acquired before and after the imaging sequence simultaneously with the invasive pressure measurement to investigate agreement between the techniques. Compliance was calculated as the slope of the best linear fit through the pressure volume data points. Distensibility was calculated by dividing the compliance by the diastolic aneurysmal volume. Young's moduli were estimated from the compliance data., Results: The AAA maximal diameter was 5.8 +/- 0.6 cm. A strong linear relation between the pressure and volume data was found. Distensibility was 1.8 +/- 0.7 x 10(-3) kPa(-1). Average compliance was 0.31 +/- 0.15 mL/kPa with accompanying estimates for Young's moduli of 9.0 +/- 2.5 MPa. Brachial cuff measurements demonstrated an underestimation of 5% for systolic (P < .001) and an overestimation of 12% for diastolic blood pressure (P < .001) compared with the pressure measured within the aneurysm., Conclusion: Distensibility and compliance of the wall of the aneurysm were determined in humans by simultaneous intra-aneurysmal pressure and volume measurements. A strong linear relationship existed between the intra-aneurysmal pressure and the volume change of the AAA. Brachial cuff measurements were significantly different compared with invasive intra-aneurysmal measurements. Consequently, no absolute distensibility values can be determined noninvasively. However, because of a constant and predictable difference between directly and indirectly derived blood pressures, MRI-based monitoring of aneurysmal distensibility may serve the online rupture risk during follow-up of aneurysms.

Anti-CD20 monoclonal antibody (rituximab) is effectively used in the treatment of B-cell lymphomas. Recent reports in the literature suggest that antibody associated autoimmune disorders may respond to rituximab. We therefore treated nine patients with anti-Hu or anti-Yo associated paraneoplastic neurological syndromes (PNS) with a maximum of four monthly IV infusions of rituximab (375mg/m(2)). In this uncontrolled, unblinded trial of rituximab, three patients improved > or =1 point on the Rankin Scale (RS). One patient with limbic encephalitis improved dramatically (RS from 5 to 1). Further studies of rituximab in autoantibody associated PNS are warranted.

Thrombocytopenia is a well-known side effect following intramuscular gold therapy in patients with rheumatoid arthritis. Thrombocytopenia may occur at any time and it can be irreversible and sometimes fatal despite cytotoxic or immunosuppressive therapy. We describe two patients who presented with haemorrhagic diathesis on the day after the administration of aurothioglucose. The thrombocytopenia in these patients was caused by aurothioglucose-induced antibody-mediated platelet destruction. Both patients made an uneventful recovery and the platelet count returned to normal within several weeks without further treatment. Antibody-detecting tests were repeated five years later and could not demonstrate the presence of antibodies. Also after incubation with aurothioglucose no antibodies could be demonstrated.

Background: A limited number cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy followed by involved field radiotherapy is the treatment of choice for Ann Arbor stage I intermediate or high grade non-Hodgkin's lymphomas (NHL). The optimal radiotherapy dose in this combined modality setting, resulting in maximal disease control with minimal toxicity is unknown. In this retrospective single-center study we evaluated the results of a combined modality treatment strategy that adapts the radiotherapy dose to the response after chemotherapy, and focus on the influence of radiotherapy dose on local control and survival., Patients and Methods: One hundred and forty patients with NHL Ann Arbor stages I/IE of intermediate or high grade malignancy received four cycles of CHOP chemotherapy followed by involved field radiotherapy (IF-RT). The radiotherapy dose for patients in complete response (CR) after CHOP was either 26 or 40 Gy. Patients in partial response (PR) after CHOP always received 40 Gy. The influence of the radiotherapy dose on treatment outcome was evaluated for patients in CR at the end of treatment (n=128)., Results: CR rates after chemotherapy and after radiotherapy were 67 and 91%, respectively. Seventy-four of the patients in CR after CHOP received 26 Gy, 20 patients in CR after CHOP 40 Gy. All patients in PR after CHOP (n=34) received 40 Gy. The localization of relapse (within or outside the radiation field) did not differ between patients receiving 26 or 40 Gy. Overall survival (OS) at 5 years for patients in CR after CHOP who received 26 and 40 Gy and for patients in PR after CHOP but CR after 40 Gy IF-RT was 76, 100 and 75%, respectively, (P=0.16), disease free survival (DFS) at 5 years 69, 90 and 75%, respectively, (P=0.52)., Conclusions: No statistically significant differences in patterns of relapse or survival were found between patients receiving 26 or 40 Gy IF-RT, however the number of events in all subgroups was small.

This study involved 12 patients with multiple myeloma (MM), in whom malignant plasma cells did not contain immunoglobulin heavy chain (IgH) protein chains. Southern blot analysis revealed monoallelic J(H) gene rearrangements in 10 patients, biallelic rearrangement in 1 patient, and biallelic deletion of the J(H) and C(micro) regions in 1 patient. Heteroduplex polymerase chain reaction analysis enabled the identification and sequencing of 9 clonal J(H) gene rearrangements. Only 4 of the joinings were complete V(H)-(D)-J(H) rearrangements, including 3 in-frame rearrangements with evidence of somatic hypermutation. Five rearrangements concerned incomplete D(H)-J(H) joinings, mainly associated with deletion of the other allele. Curiously, in at least 1 of these 5 cases the second allele seemed to be in germline configuration, whereas the in-frame V(kappa)-J(kappa) gene rearrangements contained somatic mutations. The configuration of the IGH genes was further investigated by use of C(H) probes. In 5 patients the rearrangements in the J(H) and C(H) regions were not concordant, probably caused by illegitimate IGH class switch recombination (chromosomal translocations to 14q32. 3). These data indicate that in many IgH(-) MM patients illegitimate IGH class switch rearrangement or illegitimate deletion of the functional V(H)-(D(H))-J(H) allele are responsible for IgH negativity. For example, the exclusive presence of D(H)-J(H) rearrangements in combination with mutated IGK genes can only be explained in terms of normal B-cell development, if the second (functional) IGH allele is deleted, which was probably the case in most patients. Therefore, defects at the DNA level are responsible for the lack of IgH protein production in most IgH(-) MM patients.

Purpose: Long-term survivors of Hodgkin's disease who received mantle-field irradiation at a young age have a strongly increased risk of developing breast cancer. The purpose of this study was to investigate whether this increased risk was substantially greater among women heterozygous for a germline mutation in the ataxia-telangiectasia gene (ATM)., Materials and Methods: Thirty-two patients were selected who had developed breast cancer at least 10 years following irradiation for Hodgkin's disease before the age of 45 years. In these patients, the complete open reading frame of the ATM gene was analysed for the presence of germline mutations using the protein truncation test and two mutation-specific tests, followed by genomic sequencing., Results: No A-T disease causing germline mutations were found in these selected Hodgkin patients. However, several alternative splicing events were detected which might influence protein expression levels., Conclusions: The data suggest that truncating mutations in the ATM gene are not a major component underlying the increased risk of breast cancer following Hodgkin's disease.

Objective: To study the efficacy of a single cycle of 2-chlorodeoxyadenosine (2-CDA) given as a 2-hour infusion on 5 consecutive days, in patients with hairy cell leukaemia (HCL)., Design: Non-randomised phase II study in an unselected population., Setting: 20 centres in the Netherlands and Belgium., Methods: Response to treatment was evaluated in 23 patients with a minimum follow-up of 6 months. All patients had proven HCL, were untreated or pretreated with splenectomy and (or) IFN alpha, and had at least one of the following criteria: Hb < 7.3 mmol/l, neutrophils < 1.0 x 10(9)/l, platelets < 100 x 10(9)/l, systemic symptoms or symptomatic splenomegaly. Patients with an active infection were ineligible. Treatment consisted of one cycle of 2-CDA (2-hour i.v. infusion days 1-5, dosage 0.1 mg/kg/day)., Results: Sixteen patients had received no prior treatment. At the 4-week evaluation, most patients (17/23) had improvement in one or two haematological parameters. After 6 months, 6/23 (26%) patients were in haematological remission and 13/23 (57%) were in complete remission. No patient developed progressive disease. Febrile neutropenia developed in 12/23 (52%) patients, with documented infection in three of them. A generalised rash was seen in 9/23 (39%) patients., Conclusion: 2-CDA appears to be the treatment of choice in patients with HCL. With a single 5-day cycle, over 80% of patients achieved remission.

After bone marrow transplantation (BMT), a prolonged dysregulation of humoral immunity can be observed. In the present study, we investigated whether this is reflected in an abnormal production of specific antibodies (Ab) to the T-cell-dependent recall antigen tetanus-toxoid (TT). The study group consisted of children receiving transplants of an unmodified allogeneic graft and of adults receiving either a T-cell-depleted allogeneic or an unmodified autologous BM graft. Findings were compared with those in healthy controls. In pediatric graft recipients, who were routinely revaccinated early after BMT, the Ab response was quantitatively superior to that in adult graft recipients who did not receive early revaccination. In the majority of graft recipients, the time period after vaccination required to reach the peak level of antibodies was prolonged and the number of responding TT-specific B-cell clones was markedly decreased in comparison with controls. In controls, a low frequency of dominant B-cell clones may produce low quantities of homogeneous Ab components (H-Ab) against a heterogeneous background. However, in BM graft recipients, "overshooting" of Ab production by separate B-cell clones was observed, resulting in the development of H-Ab at a relatively high concentration. These abnormalities were present up to 10 years after BMT, irrespective of either the age of the recipient, the modulation of the graft, or the vaccination schedule used. It is hypothesized that the dysregulated Ab production is the consequence of activation of a restricted number of resting memory B cells, present in germinal centers, repopulating gradually after BMT. Our data show that routine revaccination early after BMT improves the humoral immune response. However, because of a clonally dysregulated Ab production, long-lasting qualitative defects may be present even after normalization of Ab titers.

An 82-year-old man with a low-grade malignant non-Hodgkin lymphoma and an IgG3 lambda monoclonal gammopathy presented a recently acquired bleeding tendency, characterized by recurrent epistaxis, easy bruising, and episodes of melena, requiring packed red blood cell transfusions. Coagulation studies showed a von Willebrand factor (vWF) defect (Ivy bleeding time, > 15 minutes; vWF antigen [vWF:Ag], 0.08 U/mL; ristocetin cofactor activity [vWF:RCoF], < 0.05 U/mL; collagen binding activity [vWF:CBA], 0.01 U/mL; absence of the high molecular weight multimers of vWF on multimeric analysis). Mixing experiments suggested the presence of an inhibitor directed against the vWF:CBA activity of vWF without significantly inhibiting the FVIII:C, vWF:Ag, and vWF:RCoF activities. The inhibitor was identified as an antibody of the IgM class by immunoabsorption of vWF and inhibitor-vWF complexes from the plasma of the patient. Subsequent immunoprecipitation experiments using recombinant fragments of vWF showed that the inhibitor reacted with both the glycoprotein Ib binding domain (amino acids [aa] 422-826) and the A3 (aa 909-1112) domain of vWF, but not with the A2 (aa 716-908) or D4 (aa 1183-1535) domains. We conclude that the IgM autoantibody inhibits the vWF:CBA activity by reacting with an epitope present on both the glycoprotein Ib and A3 domains of vWF.

We generated a new lymphoma cell line carrying the translocations (8;14) and (14;18) and studied the genomic organization and expression of the BCL-2 and MYC genes. Polymerase chain reaction (PCR) and Southern analysis showed that the breakpoints of t(14;18) were located in the major breakpoint region (mbr) of the BCL-2 gene and just 5' of JH6 in the IgH locus. The breakpoints of the t(8;14) were located upstream of exon 2 in the non-coding region of the MYC gene and near the switch region of the IgH locus. Both IgH loci were involved in chromosomal translocations resulting in the absence of a functional B-cell receptor. Normal BCL-2 and truncated MYC transcripts were detected in these cells. The BCL-2 protein was expressed.

An 82-year-old patient with acquired von Willebrand's disease in association with a non-Hodgkin's lymphoma and a benign IgG-lambda monoclonal paraproteinemia is described with severe recurring nasopharyngeal bleedings, who responded poorly to desmopressin (DDAVP) and factor VIII/von Willebrand factor concentrates but was successfully treated with high-dose e intravenous gamma-globulin therapy.

CD30-positive anaplastic large cell lymphoma (ALCL), also known as Ki-1 lymphoma, was first described in 1985 as a new histological subtype, and was added to the updated Kiel classification in 1988. It is regarded as a process of high-grade malignancy, mainly on histological grounds. This review describes clinical features in 255 patients. There is a bimodal age distribution, with peaks in adolescence and old age. The male/female ratio is approximately 3:2. About one-third of patients present with extranodal disease. Especially the skin is often involved (two-thirds of all extranodal localisations). The tumours generally have an aggressive clinical behaviour, as in other lymphomas of high-grade malignancy. Especially the high relapse rate seems responsible for the unfavourable prognosis in these patients. However, patients with disease limited to the skin (skin-only presentation) tend to have a slower, protracted course, recalling that of the low-grade lymphomas. We conclude that, also on clinical grounds, CD30-positive ALCL is a distinct entity, in which, based on localisation of the disease, two subgroups can be discriminated with different clinical behaviour.

This paper reports the detection of residual lymphoma cells in blood and bone marrow samples from patients with translocation (t) (14;18) positive non-Hodgkin's lymphoma by the polymerase chain reaction (PCR) compared with conventional staging techniques. In 15 of 22 samples, in which no lymphoma cells could be detected by morphological examination, t(14;18) positive cells were detected by PCR. In 13 of 21 samples, in which a monoclonal B-cell population was not detectable by immunological marker analysis, PCR was positive. The clinical status (physical examination, imaging techniques, leucocyte count, and occasionally morphology and immunological marker analysis) was documented in 30 patients at the time of PCR analysis. In three of 19 patients with clinical evidence of disease, circulating t(14;18) positive cells were not detectable by PCR. Five of 11 patients in clinical remission from 7 to 47 months, showed t(14;18) positive cells in the blood. Our data show that PCR analysis in t(14;18) positive non-Hodgkin's lymphoma offers a powerful tool in the study of residual disease.

Genetic alterations that lead to the clonal expansion of differentiated cells in multiple myeloma have still to be elucidated. Many chromosomal aberrations have been found, but until now, none of them is typically associated with multiple myeloma. In search for genetic defects in multiple myeloma we studied the structure and expression of the c-myc oncogene and the pvt-like region because of their frequent association with other B-cell malignancies. Here we report co-amplification of the c-myc oncogene and the 5' part of the pvt-like region in two out of 26 cases of multiple myeloma. In both cases only kappa-light chains were produced. The amplification also manifested itself at the RNA level. Total RNA was analysed in one of these two cases showing abundant c-myc mRNA. In the same RNA sample we also detected a strong hybridizing band of about 7 kb, when the pSS.4 probe, representing the 5' part of the pvt-like region, was used. This band was not present in total RNA from normal bone marrow cells or bone marrow from multiple myeloma patients without the amplification of c-myc and the pvt-like region. Until now, transcripts of the pvt-like region were only found in a few human cell lines ranging in size from 1 to 11 kb. This is the first case in which a high expression of a +/- 7 kb transcript of the pvt-like region has been found in freshly obtained tumor material probably due to a pvt-amplification. The occurrence of abnormalities in the c-myc and the pvt-like region in multiple myeloma is a rare event and may be associated with the progression of this type of tumor.

In non-Hodgkin's lymphoma, chromosome abnormalities are found that are characteristic for the type of the lymphoma. These chromosomal abnormalities provide a tumour-specific marker and seem to play a role in the oncogenesis of the lymphoma. Chromosome 14 is involved in many lymphomas. The immunoglobulin heavy chain gene and the alpha and delta chain genes for the T cell receptor are located on this chromosome, genes which are essential for the function of B or T lymphocytes. These genes are involved in the specific translocations seen in non-Hodgkin's lymphoma. Their role and the role of oncogenes in the oncogenesis of non-Hodgkin's lymphoma are discussed. The oncogene tcl-1 is also located on chromosome 14.

A series of 60 acute nonlymphocytic leukemias (ANLL) was analyzed for the expression of terminal deoxynucleotidyl transferase (TdT). The detected TdT+ cells were studied in detail by use of double marker analyses for TdT and differentiation markers, such as myeloid markers (CD13 and CD33), B cell markers, T cell markers, and the precursor antigen CD34. In 15 (25%) of these leukemic cell samples, we found no TdT+ cells or low percentages of CD10+TdT+ cells; the latter probably represent precursor B cells. In the other 45 (75%) ANLL myeloid marker+TdT+ CD10- cells were detected, ranging from 0.1-10% (n = 24) or over 10% (n = 21) of mononuclear cells. Interestingly, a higher frequency of CD34 positivity was found on the TdT+ cells as compared to the TdT- cells, suggesting that the TdT+ cells represent an immature leukemic subpopulation. Therefore, it may be speculated that the TdT+ subpopulation contains the clonogenic ANLL cells. In two patients, in whom immunologic marker analysis was performed at initial diagnosis as well as at relapse, an expansion of the TdT+ subpopulation was documented at relapse, which may reflect a reduced differentiation capacity of the leukemic cells. Previous studies on a series of nonleukemic bone marrow and blood samples revealed that normal counterparts of myeloid marker+TdT+ cells are rare in bone marrow (less than 0.03%, if they occur at all) and that such cells are not detectable in blood. Therefore myeloid marker TdT double stainings may be useful to monitor the TdT+ leukemic subpopulation in patients with a TdT+ ANLL during and after chemotherapy. Our preliminary results on the follow-up of two such patients support this hypothesis.

The ultrastructural, light microscopical and immunological features of twelve cases of acute childhood leukemia are described. Nine cases were unclassifiable by light microscopy, morphology and cytochemistry, and three were difficult to classify because of a low percentage of Sudan-Black B positive blasts. By means of electron microscopy (including peroxidase cytochemistry), two main groups were seen: 1. Acute myeloid leukemia, in which could be distinguished a) a more differentiated myeloid leukemia, b) a leukemia with megakaryoblastic involvement and c) a minimally differentiated acute myeloid leukemia with granules present and 2. lymphoblastic leukemia. One case could not be classified. The first group included two possible cases of a hybrid leukemia with CD19 or CD10 positivity as well as ultrastructural peroxidase activity. We conclude that electron microscopy aids to further classification of minimally differentiated and hybrid acute leukemias.

In 22 transplant patients who received T cell-depleted allogeneic bone marrow (alloBMT) we investigated the chimeric state using a mixed agglutination technique and isoenzyme determinations for the red cell lineage, an isoenzyme assay for the myeloid cells, immunoglobulin allotyping for B lymphocytes and cytogenetics for karyotyping. The median duration of follow-up for these patients was 25 months after BMT. Chimerism was evaluated after 6 months. In 14 (64%) of the 22 patients incomplete chimerism was found when the results of the different techniques were combined. Recipient type cells were detected in the red cell lineage in 36% of cases, recipient type myeloid cells in 7% of cases and recipient type mitotic cells in 25% of cases where the marker could provide discrimination. In 100% of the evaluable patients recipient type immunoglobulins persisted after BMT. The data indicate a high frequency of incomplete chimerism following T cell-depleted BMT which involved the broad series of hematological lineages. This frequency appears higher than that following non-T cell-depleted BMT.